_:b429914680 . _:b7430127 . . _:b429914812 . . . _:b429914585 . _:b429914523 . _:b7430020 . _:b429914746 . _:b7429956 . _:b7429959 . _:b429914679 . . . _:b429914859 . _:b429914803 . _:b7430040 "SD (Dalziel et al. >>1986<<; Ontiveros et al. 2003), JHM cl-2 (Taguchi et al. 1985), and JHM-DL (Wang et al. 1992)." . . _:b7430009 . _:b429914668 . . . _:b429914572 . . . _:b429914734 . _:b7430029 . . . . . . _:b429914504 . _:b429914824 . _:b7429998 "receptor for MHV has been identified as CEACAM1a (also referred to as mmCGM1, BGP1a, and CD66a) belonging to the carcinoembryonic antigen family of cell adhesion molecules within the immunoglobulin superfamily (Williams et al. >>1990<<, 1991). CEACAM1a is a multifunctional protein shown to play diverse roles in a variety of cellular processes, including intercellular adhesion, tumor suppression, angiogenesis, and immune cell signaling (Gray-Owen and Blumberg 2006;" . _:b7430081 "A recent study proposes that the E protein of SARS-CoV may disrupt ion homeostasis in the host cell and that pro-apoptotic effects attributed to E (An et al. >>1999<<) could result from membrane depolarization resulting from such ionic disturbances (Pervushin et al. 2009)." . _:b7430186 "Studies using B cell-deficient mice further support a role for antibody in preventing epitope escape (Butler et al. >>2007<<). The S510 epitope escape mutants isolated from persistently infected suckling mice displayed increased morbidity and mortality compared to parental JHM upon infection of naive suckling mice, suggesting that the escape from the response" . _:b7429946 . _:b429914820 . _:b7430025 "Paul Masters (Koetzner et al. 1992; Kuo et al. >>2000<<), allows the exchange of viral genes and insertion of site-directed targeted mutations within the 3\u2032 one third of the genome encoding the viral structural genes (Fig." . _:b429914611 . _:b7429958 . _:b429914539 . _:b7430079 . . _:b429914601 . _:b429914766 . . _:b7429966 . . _:b429914623 . . . _:b7430033 . _:b7430164 "the GP33 epitope of lymphocytic choriomeningitis virus (LCMV), it was shown that adoptive transfer of naive, GP33-specific CD8 T cells resulted in lower viral titers and reduced antigen distribution in the brain (Chua et al. >>2004<<). Further studies using this adoptive transfer model revealed that increasing the number of naive, virus-specific CD8 T cells, either before infection or at early times post-infection, reduced viral replication and spread throughout the" . _:b429914774 . _:b7430032 . . _:b7430152 "The spike gene has been demonstrated to be a determinant of neurovirulence and to influence macrophage, but not T cell, infiltration into the brain (Phillips et al. 1999, 2002; Rempel et al. 2004a; Iacono et al. >>2006<<). Analysis of recombinant chimeric A59/JHM viruses was carried out to determine if the spike and/or background genes determined these differences in inflammatory cell infiltrates and chemokine expression." . _:b429914622 . _:b429914830 . _:b7430115 "macro domain with a very weak phosphatase activity; furthermore, the binding of poly-ADP-ribose polymerase (PARP-1) to Sindbis nsp3 outside of the macro domain is believed to regulate transcription in neuronal cells (Park and Griffin 2009a, b). Though the role of the ADRP in coronavirus replication and/or pathogenesis is poorly understood, the activities associated with macro domains may vary among coronavirus groups, as a recent report suggests that the macro domain of" . _:b429914796 . _:b429914732 . . . . . . . _:b7429946 "Thus, studies of MHV-induced demyelination have utilized either neuroattenuated variants of JHM, such as 2.2-V-1 (Fleming et al. >>1986<<; Marten et al. 2000b), the less neurovirulent A59 strain (Lavi et al. 1984b; MacNamara et al. 2005a), or infection of passively immunized suckling mice (Pewe et al. 1996)." . _:b7429926 . _:b429914664 . . _:b7429925 . . _:b7429933 . . _:b7429983 . _:b7430031 "SD (rA59/SJHM) confers high neurovirulence on the resulting virus (Phillips et al. >>1999<<; Navas and Weiss 2003)." . . . . . _:b7430185 "studies showed that increased levels of MHV-specific antibody in the CNS reduced the emergence of MHC class I-restricted epitope escape mutants by preventing the onset of chronic disease in the suckling mouse model (Dandekar et al. >>2003<<). Studies using B cell-deficient mice further support a role for antibody in preventing epitope escape (Butler et al. 2007)." . _:b429914541 . _:b429914514 . _:b7430190 . _:b7429959 "immunocompetent mice into RAG-deficient mice restores demyelination, which is associated with extensive recruitment of activated macrophages and microglia to the sites of spinal cord demyelination (Wang et al. 1990; Wu and Perlman >>1999<<). Furthermore, transfer of either CD4 or CD8 T cells also restores the development of demyelination in RAG-deficient mice, perhaps by triggering astrocytes to produce chemokines (Lane et al. 1998)." . . _:b7430109 "Together, the putative CPD domain and the ADRP domain could potentially participate in a pathway of nucleotide processing (Gorbalenya et al. 1991; Snijder et al. >>2003<<) in which the CPD would convert ADP-ribose-1\u2033,2\u2033-cyclic phosphate into ADP-ribose 1\u2033 phosphate and the ADRP would convert the product of the CPD, ADP-ribose 1\u2033 phosphate, into ADP-ribose and inorganic phosphate (Putics et al. 2005, 2006b)." . . . _:b7430134 "Both the numbers and types of infiltrating cells and the chemokines secreted are dependent on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. >>2001<<; Glass et al. 2002; Rempel et al. 2004b; Bergmann et al. 2006; Iacono et al. 2006; Savarin et al. 2008; Scott et al. 2008)." . _:b429914892 . . _:b429914620 . _:b429914487 . . . _:b429914707 . _:b7429943 . _:b7430157 . _:b7430186 . _:b7429943 "resulting from A59 infection, are usually assessed by staining of spinal cord sections with Luxol Fast Blue and are maximal at 1\u00A0month post-infection (Lavi et al. 1984b; Das Sarma et al. 2000; Matthews et al. 2002; MacNamara et al. 2005a)." . . _:b7429981 "SD isolated from persistently infected OBL21A cells)NeuroattenuatedOlfactory bulb neuronsL1114R; CEACAM1-dependent spreadGallagher et al. (1991), Pearce et al. (1994)JHM-DLHighly lethalNeurons, glial cellsLeu1114Stohlman et al. (>>1982<<), Wang et al. (1992)2.2-V-1 (mAb escape mutant of JHM-DL)Neuroattenuated; subacute demyelinationGlial cells, primarily oligodendrocytesL1114F; CEACAM1-dependent spreadFleming et al. (1986), Wang et al. (1992)JHM cl-2Highly lethalNeurons," . _:b7430063 "1; Yokomori et al. 1989; Kienzle et al. 1990; Yokomori et al. >>1991<<; Smits et al. 2005)." . _:b429914791 . . _:b429914780 . . _:b429914603 . _:b7429948 . _:b7429937 . _:b7430086 "N plays an important role in enhancing efficiency of transcription (Compton et al. 1987) and significantly enhances recovery of infectious virus from cells transfected with genome length synthetic RNA (Grossoehme et al. >>2009<<). N has also been implicated to play a role in translation of viral mRNA (Tahara et al. 1998). Furthermore, MHV N has been reported to associate with microtubules in a neuronal cell line in vitro (Pasick et al. 1994), suggesting a" . . . . _:b7430097 "However, since nsp1 has been reported to promote host mRNA degradation (Narayanan et al. >>2008<<), it is difficult to conclude whether the effect on IFN-\u03B2 is a direct effect of nsp1 or indirect through its ability to degrade host cell mRNA." . _:b429914759 . _:b7430053 . _:b7429995 "However, despite clearance of infectious virus, viral RNA persists in the CNS and demyelination, largely immune-mediated, becomes evident around 4\u00A0weeks post-infection (Lavi et al. 1984a, b). A notable exception to this disease course is CNS infection with the highly neurovirulent JHM isolates, particularly JHM.SD, which grow to increasing titers and induce severe encephalitis that is lethal within the first week of" . . . _:b7430116 . . _:b429914686 . . _:b429914705 . _:b7430105 "However, there are conflicting data regarding the role of MHV PLP-2 as a type I IFN antagonist (Zheng et al. 2008; Frieman et al. >>2009<<), and it is possible that the MHV- and SARS-CoV-encoded proteases may differ in this activity." . _:b7429980 . . _:b7429961 "Thus, while either CD4 or CD8 T cells are sufficient to promote demyelination, neither cell type is essential (Wu et al. >>2000<<; Matthews et al. 2002)." . _:b7430101 . . _:b429914637 . _:b7430162 . . . _:b429914551 . _:b429914493 . _:b7430104 . _:b7430082 . . . _:b7430127 "In contrast to the induction of type I IFN observed in vivo in the murine CNS, MHV induces type I IFN mRNA very poorly and only at very late times after infection in murine fibroblast cell lines (Roth-Cross et al. >>2007<<, 2008). Thus, it was of interest to determine which CNS cell types produce IFN-\u03B2 in response to MHV infection." . . _:b7430057 . . . _:b7429956 "MHV-induced demyelination is characterized by inflammatory infiltrates consisting of lymphocytes and lipid-containing macrophages (Stohlman and Weiner 1981; Lavi et al. 1986a, b; Wu and Perlman >>1999<<). Using infections with the attenuated JHM 2.2-V-1 variant, it was recently demonstrated that both monocyte-derived macrophages and microglia are present in regions of demyelination and can be seen in contact with demyelinated axons," . . _:b7429951 . _:b7430191 "specific for individual viral proteins has been shown to protect against lethal MHV infection, though evidence of sublethal infection and demyelination was still detected (Buchmeier et al. 1984; Wege et al. 1984; Nakanaga et al. >>1986<<). Furthermore, infection of muMT mice with A59 showed that infectious virus was not cleared from the CNS in the absence of mature B cells, and passive transfer of A59-specific antibody into infected muMT mice subsequently decreased viral" . _:b7430096 . _:b429914849 . _:b7430099 . . _:b7430020 "with A59, JHM, and the hepatotropic MHV-3 strain when transiently transfected into hamster cells, though much less efficiently than ceacam1a; ceacam2 messenger RNA (mRNA) was also shown to be expressed in brain tissue (Nedellec et al. >>1994<<). The alternative ceacam1b allele expressed by MHV-resistant mice can similarly mediate infection with A59 when overexpressed in vitro (Dveksler et al. 1993b)." . . _:b429914692 . _:b429914489 . _:b7430070 "There were early studies both supporting and arguing against a role for HE in MHV pathogenesis (Taguchi et al. 1986; LaMonica et al. >>1991<<; Yokomori et al. 1992, 1993, 1995)." . _:b429914739 . _:b7430106 "The best characterized is the histone-associated MacroH2A, which plays a role in cell type-specific regulation of transcription (Changolkar et al. >>2008<<). MHV, as well as some other group II coronaviruses, encodes the ns2 protein in ORF2a, just downstream of the replicase gene. The ns2 protein contains a domain with high homology to a superfamily of proteins known as 2H phosphoesterases" . _:b429914851 . . . _:b7430159 . _:b7430124 "of the high mortality following MHV infection that were carried out in the absence of IFN signaling in type I interferon receptor deficient (IFNAR\u2212/\u2212) mice (Cervantes-Barragan et al. 2007; Ireland et al. 2008; Roth-Cross et al. >>2008<<). IFNAR\u2212/\u2212 mice inoculated intracranially with low doses of the neurotropic MHV strains A59 and JHM." . _:b429914712 . _:b429914906 . . _:b429914838 . . _:b429914654 . _:b7429960 . _:b429914884 . _:b7430001 "is a multifunctional protein shown to play diverse roles in a variety of cellular processes, including intercellular adhesion, tumor suppression, angiogenesis, and immune cell signaling (Gray-Owen and Blumberg 2006; Kuespert et al. >>2006<<). The ceacam1 gene is highly conserved among mammalian species, and human CEACAM1 proteins serve as receptors for a variety of pathogens, including Neisseria species and Haemophilus influenzae." . _:b7430059 . . . . . _:b429914587 . . . . . . _:b7429965 . _:b7430083 "N plays structural roles by both complexing with genomic RNA to form the capsid (Sturman et al. >>1980<<) and interacting with the viral membrane protein (M) during virion assembly (Fig." . _:b7429931 "in terms of cellular tropism, spread throughout the central nervous system (CNS), host immune response, and disease outcome, making them useful for analysis of viral and host determinants of neurovirulence (Weiss and Navas-Martin >>2005<<)." . _:b7429936 . . _:b429914813 . _:b429914594 . . _:b7430002 . . . . . . . _:b7429953 . _:b7430062 "1; Yokomori et al. 1989; Kienzle et al. >>1990<<; Yokomori et al. 1991; Smits et al. 2005)." . _:b7430048 "for CEACAM1a is associated with a less stable association of S1 and S2 such that the conformational changes that lead to fusion are more easily triggered, even in the absence of CEACAM1a (Gallagher and Buchmeier 2001; Krueger et al. >>2001<<). The important role of the HVR in neurovirulence is further supported by the observation that the neuroattenuated phenotypes of a group of monoclonal antibody escape variants of JHM." . . . _:b7430144 . . . _:b7429991 "glial cellsS310G; CEACAM1-independent spreadOntiveros et al. (2003)A59Neuroattenuated; mild encephalitis; subacute demyelination; hepatitisNeurons, glial cellsHVR deletion (52 aa); CEACAM1-dependent spreadLavi et al. (1984a, b) Fig." . . . . _:b429914589 . _:b7429922 "Several human coronaviruses have been identified, including the mild respiratory pathogens HCoV-229E (Hamre and Procknow 1966) and HCoV-OC43 (McIntosh et al. >>1967<<), an etiologic agent of croup known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. 2003; Ksiazek et al. 2003; Peiris et" . . . _:b429914593 . _:b429914798 . . . _:b7429977 "The A59 strain was isolated independently in 1961 from a mouse with leukemia (Manaker et al. >>1961<<). Table" . . _:b429914918 . . . _:b429914646 . . _:b7430021 . _:b429914650 . . _:b429914507 . _:b429914762 . _:b429914779 . _:b429914872 . _:b429914666 . _:b7430098 . _:b7430052 "SD did not confer a highly neurovirulent phenotype to the virus (Phillips et al. >>2001<<), suggesting that cooperation of several regions of spike, including the long HVR, is likely required for the high neurovirulence conferred by the JHM." . . _:b7430012 . _:b429914555 . _:b429914694 . _:b429914674 . _:b429914718 . . _:b429914648 . . . . _:b7430153 "In contrast, macrophage chemoattractant expression is elevated during rA59/SJHM infection but not during rJHM/SA59 infection, suggesting an influence by the S gene (Iacono et al. >>2006<<; Rempel et al. 2004a; Scott et al. 2008) consistent with the extensive macrophage infiltration observed in response to viruses expressing the JHM." . _:b429914638 . _:b7430118 "The coronavirus replicase protein nsp14 (p59) is a 3\u2032\u20135\u2032 exonuclease (ExoN) of the DEDD superfamily (Snijder et al. >>2003<<). Interestingly, the nsp14 protein of MHV markedly increases the fidelity of transcription of viral RNA (Eckerle et al. 2007)." . _:b7430194 . . _:b7430055 "One of these substitutions alone, L1114R, is sufficient to confer neuroattenuation and restriction to the olfactory bulbs (Gallagher et al. 1991; Tsai et al. 2003b; Pearce et al. >>1994<<). A L1114F substitution has also been identified in the spike of the 2.2-V-1 glial-tropic variant of JHM-DL (Wang et al. 1992) and in the spike of the highly attenuated soluble receptor-resistant mutant srr7 derived from JHM cl-2 (Saeki" . _:b429914904 . _:b429914781 . . _:b429914730 . _:b7430019 . _:b7430183 . . _:b7430063 . _:b7429945 "SD or JHM-DL are so highly neurovirulent that most infected animals die from acute encephalitis, leaving few survivors with which to study the late demyelinating disease (Stohlman et al. 1982; Ontiveros et al. >>2003<<). Thus, studies of MHV-induced demyelination have utilized either neuroattenuated variants of JHM, such as 2.2-V-1 (Fleming et al. 1986; Marten et al. 2000b), the less neurovirulent A59 strain (Lavi et al. 1984b; MacNamara et al. 2005a)," . _:b7430096 "There are data suggesting that the nsp1 proteins of both MHV and SARS-CoV have the ability to inhibit the synthesis and/or signaling activities of IFN-\u03B2 (Wathelet et al. >>2007<<). However, since nsp1 has been reported to promote host mRNA degradation (Narayanan et al. 2008), it is difficult to conclude whether the effect on IFN-\u03B2 is a direct effect of nsp1 or indirect through its ability to degrade host cell mRNA." . _:b429914629 "2"^^ . _:b429914736 . _:b429914628 "2"^^ . . _:b429914631 "2"^^ . . _:b429914630 "2"^^ . _:b429914634 . _:b429914625 "2"^^ . _:b7429968 "remains elevated during late disease, and the observation that antibody depletion of either CXCL10 or CCL5 results in reduced levels of demyelination suggests an important role for these chemokines (Liu et al. 2001; Glass et al. 2002, >>2004<<). Chronic activation of astrocytes during persistent infection contributes to demyelination via the secretion of macrophage and T cell chemoattractants, and it has been suggested that additional secretion of TNF-\u03B1, IL-1\u03B2, IL-6, and type 2" . _:b7429957 . _:b429914756 . _:b7429979 . _:b7430181 "studies using the glial-tropic JHM variant 2.2-V-1 revealed that CD8 T cells maintained in the CNS after viral clearance displayed a loss of ex vivo cytolytic activity while maintaining the ability to secrete IFN-\u03B3 (Bergmann et al. >>1999<<). Recent studies revealed that CD8 T cells maintain expression of programmed death 1 (PD-1) during persistence of the JHM variant 2.2-V-1 in the CNS, while expression of the PD-1 ligand B7-H1 is concurrently maintained on" . _:b429914624 "2"^^ . _:b429914627 "2"^^ . _:b7430132 "This result is in contrast to the studies described above in which IFNAR signaling was essential for control of spread of virus following intracranial inoculation (Ireland et al. 2008; Roth-Cross et al. >>2008<<). Taken together, these data suggest that type I IFN signaling in parenchymal cells may have a variable impact on spread of virus within the brain and may depend on the route of inoculation and the initial cell types infected. This idea" . _:b7430027 . _:b429914626 "2"^^ . _:b7430129 "macrophages and microglia isolated from the CNS of infected mice were shown to produce IFN-\u03B2 protein; this result was consistent with IFN-\u03B2 mRNA expression observed in cultured primary macrophages and microglia (Roth-Cross et al. >>2008<<). Infection of primary macrophages derived from the bone marrow of mice lacking expression of several pattern recognition receptors further demonstrated that MDA5 is a major sensor that recognizes MHV and triggers type I IFN expression in" . _:b429914637 "2"^^ . . . _:b429914636 "2"^^ . _:b429914724 . _:b429914639 "2"^^ . _:b7430031 . _:b429914638 "2"^^ . _:b7429947 "Thus, studies of MHV-induced demyelination have utilized either neuroattenuated variants of JHM, such as 2.2-V-1 (Fleming et al. 1986; Marten et al. 2000b), the less neurovirulent A59 strain (Lavi et al. 1984b; MacNamara et al. 2005a), or infection of passively immunized suckling mice (Pewe et al. 1996)." . _:b429914633 "2"^^ . _:b429914538 . _:b429914826 . . _:b429914632 "2"^^ . _:b429914629 . _:b429914635 "2"^^ . _:b429914628 . _:b429914643 . . _:b429914634 "2"^^ . _:b429914631 . _:b429914645 "2"^^ . _:b429914761 . _:b429914630 . _:b429914615 . _:b7429935 . _:b429914644 "2"^^ . _:b429914625 . _:b429914647 "2"^^ . _:b429914624 . _:b429914646 "2"^^ . _:b429914627 . _:b429914641 "2"^^ . _:b429914626 . _:b7429934 "MHV binds to a target cell via interaction of the spike glycoprotein with its cellular receptor CEACAM1a (Williams et al. >>1991<<) and fuses either at the cell surface or from within endosomes, likely depending on target cell type and MHV strain (Gallagher et al. 1991; Kooi et al. 1991; Nash and Buchmeier 1997)." . _:b429914640 "2"^^ . . _:b429914637 . _:b429914643 "2"^^ . _:b429914636 . _:b429914642 "2"^^ . _:b429914639 . _:b7429971 "model and strains" . _:b429914865 . _:b429914653 "2"^^ . _:b429914638 . _:b7430184 . _:b429914652 "2"^^ . _:b429914633 . _:b429914655 "2"^^ . _:b429914632 . _:b429914654 "2"^^ . _:b429914635 . _:b429914795 . _:b429914633 . _:b429914649 "2"^^ . _:b429914634 . _:b429914648 "2"^^ . _:b429914645 . . _:b429914651 "2"^^ . _:b429914644 . _:b429914650 "2"^^ . _:b429914771 . _:b429914647 . _:b429914678 . _:b429914878 . _:b429914661 "2"^^ . . . _:b429914495 . _:b429914646 . _:b429914818 . _:b429914660 "2"^^ . _:b429914641 . _:b7430189 . _:b429914663 "2"^^ . _:b429914640 . _:b429914662 "2"^^ . _:b429914643 . _:b429914657 "2"^^ . _:b7430192 "Interestingly, clearance of A59 from the livers of these mice did not require B cells (Matthews et al. >>2001<<)." . _:b429914642 . _:b429914656 "2"^^ . _:b429914787 . _:b429914653 . _:b429914681 . _:b429914659 "2"^^ . _:b7430122 . _:b429914652 . _:b429914658 "2"^^ . _:b429914655 . _:b7430120 . _:b429914595 . _:b429914669 "2"^^ . _:b429914654 . _:b429914668 "2"^^ . _:b429914649 . _:b429914671 "2"^^ . _:b429914648 . _:b429914670 "2"^^ . _:b429914651 . _:b429914665 "2"^^ . . _:b429914650 . _:b429914598 . _:b429914664 "2"^^ . _:b429914661 . . . _:b429914667 "2"^^ . _:b429914660 . _:b429914666 "2"^^ . _:b429914663 . _:b429914677 "2"^^ . _:b429914662 . _:b429914676 "2"^^ . . _:b429914657 . . _:b429914679 "2"^^ . _:b429914656 . _:b429914678 "2"^^ . _:b429914659 . . _:b429914673 "2"^^ . _:b429914658 . . _:b429914788 . _:b429914672 "2"^^ . _:b429914669 . _:b429914675 "2"^^ . _:b429914765 . _:b429914668 . _:b429914753 . _:b7430045 "The extremely high neurovirulence of these viruses is due, at least in part, to their ability to induce cell-to-cell fusion and viral spread in the absence of the receptor CEACAM1a (Gallagher et al. 1992, Dalziel et al. >>1986<<; Gallagher and Buchmeier 2001)." . _:b429914674 "2"^^ . _:b429914671 . _:b429914685 "2"^^ . _:b429914670 . . _:b429914684 "2"^^ . _:b429914665 . _:b429914687 "2"^^ . . _:b429914664 . _:b429914686 "2"^^ . _:b429914667 . _:b429914558 . _:b429914681 "2"^^ . _:b429914666 . _:b429914680 "2"^^ . _:b429914550 . _:b429914677 . _:b429914683 "2"^^ . _:b429914676 . _:b429914682 "2"^^ . _:b429914679 . _:b7430047 "lack of requirement for CEACAM1a is associated with a less stable association of S1 and S2 such that the conformational changes that lead to fusion are more easily triggered, even in the absence of CEACAM1a (Gallagher and Buchmeier >>2001<<; Krueger et al. 2001). The important role of the HVR in neurovirulence is further supported by the observation that the neuroattenuated phenotypes of a group of monoclonal antibody escape variants of JHM." . _:b429914527 . _:b429914693 "2"^^ . _:b429914678 . _:b7430195 "Furthermore, the numbers of antibody-secreting cells were shown to remain stable during persistence (Tschen et al. >>2002<<). Taken together, it is likely that T cell-mediated cytolysis, cytokine secretion, and antibody production play a collective role in clearing infectious virus and subsequently maintaining control of MHV during persistence in the CNS." . _:b429914692 "2"^^ . _:b429914673 . _:b429914695 "2"^^ . _:b429914672 . _:b429914694 "2"^^ . . _:b429914481 . _:b429914675 . _:b429914689 "2"^^ . _:b429914674 . . _:b429914688 "2"^^ . _:b429914685 . . _:b429914691 "2"^^ . . _:b429914684 . _:b429914862 . _:b429914690 "2"^^ . . _:b429914687 . _:b429914701 "2"^^ . _:b429914686 . _:b429914700 "2"^^ . _:b429914681 . _:b429914703 "2"^^ . _:b429914680 . _:b429914702 "2"^^ . _:b429914683 . _:b429914697 "2"^^ . _:b429914682 . . _:b429914696 "2"^^ . _:b429914693 . _:b429914505 . _:b429914699 "2"^^ . _:b429914692 . _:b429914698 "2"^^ . . _:b429914695 . . _:b429914709 "2"^^ . . _:b429914694 . _:b429914708 "2"^^ . . _:b429914689 . _:b7429997 _:b7430000 . . _:b7429997 _:b7430001 . _:b429914711 "2"^^ . _:b7429997 _:b7430002 . . _:b429914688 . _:b7429997 _:b7430003 . _:b7429997 _:b7430004 . _:b7429997 _:b7430005 . _:b429914710 "2"^^ . _:b7429997 _:b7430006 . _:b7429997 _:b7430007 . _:b429914691 . _:b7429997 _:b7430008 . _:b7429997 _:b7430009 . _:b429914705 "2"^^ . _:b7429997 _:b7430010 . _:b7429997 _:b7430011 . _:b429914690 . _:b7429997 _:b7430012 . _:b7429997 _:b7430013 . _:b7430139 "secreted are dependent on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. 2001; Glass et al. 2002; Rempel et al. 2004b; Bergmann et al. 2006; Iacono et al. 2006; Savarin et al. >>2008<<; Scott et al. 2008)." . _:b429914704 "2"^^ . _:b7429997 _:b7430014 . _:b7429997 _:b7430015 . _:b429914701 . _:b429914707 "2"^^ . _:b429914700 . _:b429914706 "2"^^ . _:b429914703 . _:b7429972 "2; Weiss and Navas-Martin >>2005<<). For this reason, MHV infection is commonly studied as a model for the human demyelinating disease multiple sclerosis." . _:b7430145 "SD strain suggest that this cell type can serve as a destructive force within the inflamed CNS, contributing to both destruction of the brain parenchyma and maintenance of a pro-inflammatory state (Iacono et al. >>2006<<). Not surprisingly, the observation of increased numbers of macrophages and neutrophils within the brains of JHM.SD-infected animals is consistent with higher levels of macrophage- and neutrophil-recruiting chemokines in the brain, as" . _:b429914717 "2"^^ . _:b429914702 . . _:b7430155 "In contrast, macrophage chemoattractant expression is elevated during rA59/SJHM infection but not during rJHM/SA59 infection, suggesting an influence by the S gene (Iacono et al. 2006; Rempel et al. 2004a; Scott et al. >>2008<<) consistent with the extensive macrophage infiltration observed in response to viruses expressing the JHM." . _:b7429997 _:b7429998 . _:b429914716 "2"^^ . _:b429914697 . _:b7429997 _:b7429999 . _:b429914665 . _:b429914498 . _:b429914719 "2"^^ . _:b429914696 . _:b7430081 . . _:b429914718 "2"^^ . _:b429914699 . . _:b429914713 "2"^^ . _:b7430072 "There were early studies both supporting and arguing against a role for HE in MHV pathogenesis (Taguchi et al. 1986; LaMonica et al. 1991; Yokomori et al. 1992, >>1993<<, 1995). However, these studies were not able to distinguish between the effects of HE and the influence of other genes in the comparison of various MHV isolates. It is clear that expression of the viral HE glycoprotein is not essential" . _:b429914698 . _:b429914712 "2"^^ . _:b429914709 . _:b429914715 "2"^^ . _:b429914708 . _:b429914714 "2"^^ . _:b429914711 . _:b429914725 "2"^^ . _:b429914710 . _:b429914724 "2"^^ . _:b429914705 . _:b7430099 "The nsp3 protein of SARS-CoV was shown to be a type I IFN antagonist, as measured by inhibition of expression of an NF-\u03BAB-dependent reporter plasmid (Wathelet et al. >>2007<<). The PLP of SARS-CoV and the analogous PLP-2 of MHV were also shown to have deubiquitinating activity, and it was suggested that this activity could confer a role as a type I IFN antagonist (Barretto et al. 2005; Zheng et al. 2008)." . . _:b429914727 "2"^^ . . _:b429914704 . _:b429914522 . _:b7429973 "named for Professor John Howard Mueller, was initially isolated by Cheever, Bailey, and colleagues in 1949 from the brain of a paralyzed mouse and shown to induce encephalitis with extensive destruction of myelin (Bailey et al. >>1949<<; Cheever et al. 1949). Dr. Leslie Weiner later serially passaged this virus multiple times through mouse brains (Weiner 1973; Weiner et al. 1973)." . . _:b429914726 "2"^^ . _:b429914707 . . _:b429914721 "2"^^ . _:b429914706 . . _:b429914720 "2"^^ . _:b429914717 . . _:b7430115 . _:b429914723 "2"^^ . _:b429914716 . _:b7430055 . _:b429914883 . _:b429914722 "2"^^ . _:b429914719 . _:b429914733 "2"^^ . _:b429914718 . . _:b429914732 "2"^^ . _:b429914713 . . _:b429914735 "2"^^ . _:b429914712 . . . _:b429914734 "2"^^ . _:b429914715 . _:b7430032 "SD (rA59/SJHM) confers high neurovirulence on the resulting virus (Phillips et al. 1999; Navas and Weiss >>2003<<). These studies have also demonstrated, perhaps unexpectedly, that a chimeric recombinant virus expressing the spike of the hepatotropic A59 within the background of the nonhepatotropic JHM.SD (rJHM/SA59) cannot induce hepatitis (Navas" . _:b429914729 "2"^^ . _:b429914714 . _:b429914877 . _:b429914728 "2"^^ . _:b429914725 . _:b429914731 "2"^^ . _:b429914724 . . _:b7430114 "In addition, the ADRP also has binding activity to mono- and poly-ADP-ribose, implying that it may participate in ribosylation of host cell proteins, which may promote apoptosis or necrosis (Egloff et al. >>2006<<)." . _:b429914730 "2"^^ . _:b429914727 . _:b429914741 "2"^^ . _:b429914726 . _:b429914740 "2"^^ . _:b429914721 . _:b429914582 . . _:b429914743 "2"^^ . _:b429914720 . . _:b429914656 . _:b429914895 . _:b429914742 "2"^^ . _:b429914723 . _:b7430068 . . _:b429914737 "2"^^ . _:b429914722 . _:b429914548 . _:b429914736 "2"^^ . _:b429914733 . _:b429914739 "2"^^ . _:b429914732 . _:b429914738 "2"^^ . _:b429914735 . _:b429914749 "2"^^ . . _:b429914734 . _:b7429933 "1; Lai and Stohlman 1978; Lee et al. >>1991<<). The 5\u2032 two thirds of the genome (ORF1a and ORF1b) encode the viral replicase as well as an assortment of enzymes and other nonstructural proteins, while the 3\u2032 one third of the genome (ORFs 2-7) largely encodes the structural proteins" . _:b429914748 "2"^^ . . _:b429914729 . _:b429914534 . _:b429914629 . _:b7429971 _:b7429992 . _:b7429971 _:b7429993 . _:b7429920 . _:b7429971 _:b7429994 . _:b429914751 "2"^^ . _:b429914728 . _:b7429971 _:b7429995 . _:b7429971 _:b7429996 . _:b429914750 "2"^^ . _:b429914731 . _:b429914743 . _:b7430135 "Both the numbers and types of infiltrating cells and the chemokines secreted are dependent on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. 2001; Glass et al. >>2002<<; Rempel et al. 2004b; Bergmann et al. 2006; Iacono et al. 2006; Savarin et al. 2008; Scott et al. 2008)." . _:b7429971 _:b7429984 . _:b7429971 _:b7429985 . _:b429914745 "2"^^ . _:b7429971 _:b7429986 . _:b429914730 . _:b7429971 _:b7429987 . _:b7429979 "SD isolated from persistently infected OBL21A cells)NeuroattenuatedOlfactory bulb neuronsL1114R; CEACAM1-dependent spreadGallagher et al. (>>1991<<), Pearce et al. (1994)JHM-DLHighly lethalNeurons, glial cellsLeu1114Stohlman et al. (1982), Wang et al. (1992)2.2-V-1 (mAb escape mutant of JHM-DL)Neuroattenuated; subacute demyelinationGlial cells, primarily oligodendrocytesL1114F;" . _:b7429971 _:b7429988 . _:b7429971 _:b7429989 . _:b429914744 "2"^^ . _:b7429971 _:b7429990 . _:b429914741 . _:b7429971 _:b7429991 . _:b7429997 _:b7430016 . _:b7429997 _:b7430017 . _:b429914747 "2"^^ . _:b7429997 _:b7430018 . _:b429914740 . _:b7429997 _:b7430019 . _:b429914847 . _:b7429997 _:b7430020 . _:b7429938 "Nascent nucleocapsids acquire their lipid envelopes and surface proteins via budding through internal membranes of the ER/Golgi, and newly formed virions are released at the cell surface (de Haan and Rottier >>2005<<). Fig." . _:b7429997 _:b7430021 . _:b429914746 "2"^^ . . _:b7429997 _:b7430022 . _:b429914743 . _:b429914757 "2"^^ . _:b429914742 . _:b429914756 "2"^^ . _:b429914737 . . _:b7430119 "Interestingly, the nsp14 protein of MHV markedly increases the fidelity of transcription of viral RNA (Eckerle et al. >>2007<<). Furthermore, a single amino acid substitution (Y6398H) 140 amino acids downstream of the last predicted exoribonuclease catalytic motif had no effect on replication in cell culture but conferred significant viral attenuation in mice" . _:b429914759 "2"^^ . . _:b429914736 . _:b7429942 . . _:b429914758 "2"^^ . _:b429914739 . _:b429914560 . . . _:b429914596 . _:b429914753 "2"^^ . _:b429914738 . _:b7430092 "However, this effect occurs via induction of fibrinogen-like protein 2 (fgl2; Parr et al. 1995; Ning et al. >>1999<<, 2005) by the N proteins of hepatotropic MHV-3 and A59 strains, and there is no evidence to suggest that fgl2 plays a role in CNS pathogenesis." . _:b429914597 . _:b429914598 . _:b429914599 . _:b429914752 "2"^^ . _:b429914592 . _:b429914749 . _:b429914593 . . _:b7429971 _:b7429976 . _:b429914594 . _:b429914595 . _:b7429971 _:b7429977 . _:b429914755 "2"^^ . _:b7429971 _:b7429978 . _:b429914604 . _:b429914748 . _:b7429971 _:b7429979 . _:b429914605 . _:b7429962 . _:b429914606 . _:b7430120 "a single amino acid substitution (Y6398H) 140 amino acids downstream of the last predicted exoribonuclease catalytic motif had no effect on replication in cell culture but conferred significant viral attenuation in mice (Sperry et al. >>2005<<). The precise role of this nsp14 in pathogenesis is not yet known." . _:b7429971 _:b7429980 . _:b429914607 . _:b7429971 _:b7429981 . _:b429914754 "2"^^ . _:b7430083 . _:b7429971 _:b7429982 . _:b429914600 . _:b429914751 . _:b7429971 _:b7429983 . _:b429914601 . _:b7429963 . _:b429914602 . _:b429914603 . _:b429914765 "2"^^ . _:b429914612 . _:b429914750 . _:b429914613 . _:b429914614 . _:b7429971 _:b7429972 . _:b429914615 . _:b7429971 _:b7429973 . _:b429914764 "2"^^ . _:b7430137 "of infiltrating cells and the chemokines secreted are dependent on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. 2001; Glass et al. 2002; Rempel et al. 2004b; Bergmann et al. >>2006<<; Iacono et al. 2006; Savarin et al. 2008; Scott et al. 2008)." . _:b7429971 _:b7429974 . _:b429914608 . _:b429914745 . _:b7429971 _:b7429975 . _:b429914609 . _:b429914610 . _:b429914611 . _:b429914767 "2"^^ . _:b429914620 . _:b429914744 . _:b429914621 . _:b429914622 . . _:b429914623 . _:b429914536 . _:b429914616 . _:b429914766 "2"^^ . _:b429914747 . _:b429914617 . _:b429914618 . _:b7430123 . . _:b429914619 . _:b429914761 "2"^^ . _:b429914564 . _:b429914746 . _:b429914565 . _:b429914566 . . _:b429914567 . _:b7430134 . _:b429914760 "2"^^ . . _:b429914560 . _:b429914757 . _:b7430104 "However, there are conflicting data regarding the role of MHV PLP-2 as a type I IFN antagonist (Zheng et al. >>2008<<; Frieman et al. 2009), and it is possible that the MHV- and SARS-CoV-encoded proteases may differ in this activity." . _:b429914561 . _:b429914562 . _:b7429939 _:b7429944 . _:b429914563 . _:b7429939 _:b7429945 . _:b429914763 "2"^^ . _:b7429939 _:b7429946 . _:b429914572 . _:b429914756 . _:b7430183 "bone marrow chimeras to demonstrate that antiviral CD8 T cell populations are maintained during persistence in the CNS, at least in part, by recruitment of both antigen-experienced and naive CD8 T cells from the periphery (Zhao et al. >>2009<<)." . _:b7429939 _:b7429947 . _:b429914573 . _:b429914574 . _:b7430126 . _:b7429939 _:b7429948 . . _:b7429939 _:b7429949 . _:b429914575 . _:b429914762 "2"^^ . _:b7429939 _:b7429950 . _:b429914568 . _:b429914759 . _:b7429939 _:b7429951 . _:b429914569 . . _:b429914570 . _:b429914531 . _:b429914571 . . _:b429914773 "2"^^ . _:b429914580 . _:b429914758 . _:b429914581 . _:b429914491 . . _:b429914582 . _:b7429939 _:b7429940 . _:b429914583 . _:b7429939 _:b7429941 . _:b429914772 "2"^^ . _:b7429939 _:b7429942 . _:b429914576 . _:b429914753 . _:b7429939 _:b7429943 . _:b429914577 . _:b429914578 . _:b429914811 . _:b429914579 . _:b429914775 "2"^^ . _:b429914588 . _:b429914752 . _:b429914589 . _:b429914714 . _:b429914574 . _:b429914590 . _:b429914657 . _:b429914591 . _:b429914774 "2"^^ . _:b429914584 . _:b429914755 . _:b429914585 . _:b429914586 . _:b7429966 "respectively, remains elevated during late disease, and the observation that antibody depletion of either CXCL10 or CCL5 results in reduced levels of demyelination suggests an important role for these chemokines (Liu et al. >>2001<<; Glass et al. 2002, 2004)." . _:b429914587 . _:b429914769 "2"^^ . _:b429914532 . _:b429914754 . _:b429914533 . _:b429914534 . _:b429914535 . _:b429914776 . _:b429914670 . _:b429914528 . _:b429914768 "2"^^ . _:b429914765 . _:b429914529 . _:b429914530 . _:b7430004 "These murine CEACAM1a isoforms contain either two or four extracellular immunoglobulin-like domains linked by a transmembrane domain to either a short (10 aa) or long (73 aa) cytoplasmic tail (McCuaig et al. 1992, >>1993<<). Using recombinant CEACAM1a constructs with deletions within the extracellular domains, the site of MHV binding was shown to be within the N-terminal domain (D1; Dveksler et al. 1993a). This N-terminal domain is present in all four" . _:b429914531 . _:b429914771 "2"^^ . . _:b429914540 . _:b429914764 . _:b429914541 . . _:b429914542 . . _:b429914543 . _:b429914770 "2"^^ . _:b429914536 . _:b429914767 . _:b429914627 . _:b429914537 . . _:b429914538 . . _:b429914539 . _:b429914509 . _:b429914548 . _:b429914781 "2"^^ . _:b429914766 . _:b429914549 . _:b429914550 . _:b429914551 . _:b429914780 "2"^^ . _:b429914544 . _:b429914761 . _:b429914545 . _:b429914546 . _:b429914547 . _:b429914610 . _:b429914556 . _:b429914607 . _:b429914783 "2"^^ . _:b429914760 . _:b429914557 . _:b429914558 . _:b7430012 "In the brain, only endothelial cells and microglia have been shown to express CEACAM1a protein (Godfraind et al. >>1997<<; Ramakrishna et al. 2004)." . _:b429914568 . _:b429914559 . _:b7430015 "in a CEACAM1a-independent manner; a soluble receptor-resistant mutant of cl-2 known as srr7 (Matsuyama et al. 2001) cannot spread without CEACAM1a and is thus restricted to microglia in mixed neural cultures (Nakagaki and Taguchi >>2005<<). Curiously, strain A59, which has also been shown to depend on CEACAM1a for spread (Tsai et al. 2003a; unpublished data), infects a variety of CNS cell types in vivo in addition to microglia." . . _:b429914552 . _:b429914782 "2"^^ . _:b429914763 . _:b429914553 . _:b429914554 . _:b429914555 . _:b429914777 "2"^^ . _:b429914500 . _:b429914762 . . _:b429914501 . _:b7429927 "agent of croup known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. 2003; Ksiazek et al. 2003; Peiris et al. >>2003<<; Osterhaus et al. 2004)." . _:b429914502 . _:b429914503 . _:b7429955 . _:b429914496 . _:b429914776 "2"^^ . _:b429914773 . _:b7430048 . _:b429914497 . . _:b429914498 . _:b429914836 . _:b429914499 . _:b429914779 "2"^^ . _:b7430166 . _:b429914816 . _:b429914508 . _:b429914772 . _:b429914509 . _:b429914510 . _:b429914511 . _:b429914778 "2"^^ . _:b429914504 . _:b429914775 . _:b429914505 . _:b429914506 . _:b7430027 "Characterization of isogenic recombinant MHV strains differing only in spike has definitively demonstrated the important role of spike in determining neurovirulence during infection in the mouse (Phillips et al. >>1999<<, 2002; Navas and Weiss 2003; Iacono et al. 2006)." . _:b429914507 . . _:b429914516 . _:b429914789 "2"^^ . _:b429914774 . _:b429914517 . _:b429914518 . _:b7429941 . _:b429914519 . _:b429914778 . _:b429914788 "2"^^ . _:b429914512 . _:b429914769 . _:b429914513 . _:b429914514 . _:b7429939 _:b7429960 . _:b429914515 . _:b7429939 _:b7429961 . _:b429914920 . _:b7430195 . _:b7429939 _:b7429962 . _:b429914524 . _:b429914791 "2"^^ . _:b429914768 . _:b7429939 _:b7429963 . _:b429914525 . _:b429914689 . _:b7429939 _:b7429964 . _:b429914526 . _:b429914527 . _:b7429939 _:b7429965 . _:b429914790 "2"^^ . _:b7429939 _:b7429966 . _:b429914520 . _:b429914771 . _:b7429939 _:b7429967 . _:b429914521 . _:b429914522 . _:b7430131 . _:b7429939 _:b7429952 . _:b429914523 . _:b7430165 . _:b7430011 "CEACAM1a is highly expressed on epithelia, endothelia, and cells of hematopoietic origin, including macrophages, B cells, and activated T cells (Coutelier et al. 1994; Godfraind et al. 1995; Nakajima et al. >>2002<<). In the brain, only endothelial cells and microglia have been shown to express CEACAM1a protein (Godfraind et al. 1997; Ramakrishna et al. 2004). Yet, perhaps paradoxically, many neurotropic MHV strains are able to infect a wide range of" . _:b7429939 _:b7429953 . _:b429914785 "2"^^ . _:b7429939 _:b7429954 . _:b7429977 . _:b429914770 . _:b7429939 _:b7429955 . . _:b7429939 _:b7429956 . _:b7429939 _:b7429957 . _:b429914784 "2"^^ . _:b7429939 _:b7429958 . _:b429914781 . _:b7429939 _:b7429959 . _:b429914502 . _:b429914476 . _:b429914787 "2"^^ . _:b429914780 . _:b429914477 . . _:b429914478 . _:b429914479 . _:b429914786 "2"^^ . _:b429914783 . _:b7429939 _:b7429968 . _:b429914475 . _:b7429939 _:b7429969 . _:b429914797 "2"^^ . _:b7429939 _:b7429970 . _:b429914484 . _:b429914782 . _:b429914485 . _:b429914486 . _:b429914626 . _:b7430107 . _:b429914487 . _:b429914796 "2"^^ . _:b429914480 . _:b429914777 . _:b429914481 . _:b429914482 . _:b429914483 . _:b429914799 "2"^^ . _:b429914492 . _:b429914776 . _:b429914493 . _:b429914494 . _:b429914495 . _:b7430109 . _:b429914798 "2"^^ . _:b429914488 . _:b429914779 . _:b429914489 . . _:b429914490 . _:b429914491 . _:b429914793 "2"^^ . _:b429914778 . _:b429914792 "2"^^ . _:b429914789 . _:b429914767 . _:b429914561 . _:b429914795 "2"^^ . _:b429914788 . _:b429914652 . _:b429914794 "2"^^ . _:b429914791 . . _:b429914805 "2"^^ . _:b429914790 . . _:b429914519 . _:b429914804 "2"^^ . _:b429914785 . . _:b429914807 "2"^^ . _:b429914784 . _:b7430090 "SD N is a determinant of high neurovirulence, as a chimeric virus expressing the JHM N within the A59 background is significantly more neurovirulent than the parental A59 (Cowley et al. >>2010<<). While the mechanism of this enhanced neurovirulence is unclear, our data suggest that it is unlikely to involve enhanced axonal transport or the role of N as an interferon antagonist. Interestingly, N has been implicated as an important" . . . _:b429914806 "2"^^ . _:b429914787 . _:b7429958 "from infected immunocompetent mice into RAG-deficient mice restores demyelination, which is associated with extensive recruitment of activated macrophages and microglia to the sites of spinal cord demyelination (Wang et al. >>1990<<; Wu and Perlman 1999). Furthermore, transfer of either CD4 or CD8 T cells also restores the development of demyelination in RAG-deficient mice, perhaps by triggering astrocytes to produce chemokines (Lane et al. 1998)." . _:b7429919 _:b7429936 . _:b7429919 _:b7429937 . _:b7430016 "Curiously, strain A59, which has also been shown to depend on CEACAM1a for spread (Tsai et al. 2003a; unpublished data), infects a variety of CNS cell types in vivo in addition to microglia." . _:b429914897 . _:b7429919 _:b7429938 . _:b429914636 . _:b429914801 "2"^^ . _:b429914786 . _:b429914841 . _:b429914800 "2"^^ . _:b429914797 . _:b7429919 _:b7429928 . _:b7429919 _:b7429929 . _:b429914803 "2"^^ . _:b7429919 _:b7429930 . _:b429914796 . _:b7429919 _:b7429931 . _:b7429919 _:b7429932 . . _:b7429919 _:b7429933 . _:b429914802 "2"^^ . _:b7429919 _:b7429934 . _:b429914799 . _:b7429919 _:b7429935 . _:b7429984 "et al. (1982), Wang et al. (1992)2.2-V-1 (mAb escape mutant of JHM-DL)Neuroattenuated; subacute demyelinationGlial cells, primarily oligodendrocytesL1114F; CEACAM1-dependent spreadFleming et al. (1986), Wang et al. (>>1992<<)JHM cl-2Highly lethalNeurons, glial cellsGly310; Leu1114; CEACAM1-independent spreadTaguchi et al. (1985)srr7 (soluble receptor-resistant mutant of JHM cl-2)NeuroattenuatedMacrophages/microglia (in vitro)L1114F; CEACAM1-dependent" . _:b7429919 _:b7429920 . _:b7429919 _:b7429921 . _:b429914813 "2"^^ . _:b7430071 . _:b7429919 _:b7429922 . _:b429914798 . _:b7429919 _:b7429923 . _:b7429924 "have been identified, including the mild respiratory pathogens HCoV-229E (Hamre and Procknow 1966) and HCoV-OC43 (McIntosh et al. 1967), an etiologic agent of croup known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. >>2005<<), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. 2003; Ksiazek et al. 2003; Peiris et al. 2003; Osterhaus et al. 2004)." . _:b7429919 _:b7429924 . _:b7429919 _:b7429925 . _:b7429919 _:b7429926 . _:b429914812 "2"^^ . _:b7429919 _:b7429927 . _:b429914793 . _:b429914815 "2"^^ . _:b429914792 . . _:b429914814 "2"^^ . _:b429914795 . _:b7430007 . _:b429914809 "2"^^ . _:b429914794 . _:b429914885 . . _:b429914808 "2"^^ . _:b429914805 . _:b7429948 "Thus, studies of MHV-induced demyelination have utilized either neuroattenuated variants of JHM, such as 2.2-V-1 (Fleming et al. 1986; Marten et al. 2000b), the less neurovirulent A59 strain (Lavi et al. 1984b; MacNamara et al. 2005a), or infection of passively immunized suckling mice (Pewe et al. 1996). The use of these models ensures enough survivors of acute infection to allow the study of demyelination." . _:b429914811 "2"^^ . _:b429914804 . . _:b429914729 . _:b7429937 "with its cellular receptor CEACAM1a (Williams et al. 1991) and fuses either at the cell surface or from within endosomes, likely depending on target cell type and MHV strain (Gallagher et al. 1991; Kooi et al. 1991; Nash and Buchmeier >>1997<<). Following entry, viral replication occurs in the cytoplasm." . _:b7430064 . _:b429914810 "2"^^ . _:b429914807 . _:b429914777 . . _:b429914821 "2"^^ . _:b429914806 . . _:b429914820 "2"^^ . _:b429914801 . _:b429914871 . _:b429914823 "2"^^ . _:b429914800 . _:b429914822 "2"^^ . _:b429914803 . _:b429914817 "2"^^ . _:b429914852 . _:b429914802 . _:b429914853 . . _:b429914854 . . _:b429914855 . . _:b429914848 . _:b429914816 "2"^^ . _:b429914813 . _:b429914849 . _:b429914850 . . _:b429914851 . _:b429914520 . _:b429914860 . _:b429914819 "2"^^ . _:b429914812 . _:b429914861 . _:b429914862 . _:b429914863 . _:b7430004 . _:b429914856 . _:b429914818 "2"^^ . _:b429914815 . _:b429914857 . _:b429914858 . _:b429914859 . _:b429914829 "2"^^ . _:b429914868 . _:b429914814 . _:b429914869 . . _:b429914870 . _:b429914871 . _:b429914828 "2"^^ . _:b429914864 . _:b429914809 . _:b429914865 . _:b429914866 . _:b429914867 . _:b7430092 . _:b429914831 "2"^^ . _:b429914876 . _:b429914808 . _:b429914877 . . _:b429914878 . . _:b429914879 . _:b429914617 . _:b429914872 . _:b429914830 "2"^^ . _:b429914811 . _:b429914873 . . _:b429914874 . _:b429914875 . _:b429914735 . _:b429914820 . _:b429914825 "2"^^ . _:b429914810 . _:b7430043 "SD (Dalziel et al. 1986; Ontiveros et al. 2003), JHM cl-2 (Taguchi et al. 1985), and JHM-DL (Wang et al. >>1992<<). The extremely high neurovirulence of these viruses is due, at least in part, to their ability to induce cell-to-cell fusion and viral spread in the absence of the receptor CEACAM1a (Gallagher et al. 1992, Dalziel et al. 1986; Gallagher" . _:b429914821 . . _:b429914822 . _:b429914823 . _:b429914824 "2"^^ . _:b429914816 . _:b429914821 . _:b429914817 . . _:b429914818 . _:b429914819 . . _:b429914828 . _:b429914827 "2"^^ . . . _:b429914820 . _:b429914829 . _:b429914830 . _:b429914831 . _:b429914826 "2"^^ . _:b429914824 . _:b429914823 . _:b429914825 . . _:b429914826 . _:b429914827 . _:b429914837 "2"^^ . _:b429914836 . _:b429914822 . _:b429914837 . _:b429914838 . _:b429914839 . _:b429914836 "2"^^ . _:b429914832 . _:b429914817 . _:b429914833 . _:b429914834 . _:b429914835 . _:b429914839 "2"^^ . _:b429914844 . _:b429914816 . _:b429914845 . . _:b429914846 . _:b7430102 . _:b429914575 . _:b429914847 . _:b429914838 "2"^^ . _:b429914840 . _:b429914819 . _:b429914841 . _:b429914842 . _:b429914843 . _:b7430118 . _:b429914477 . _:b429914788 . _:b429914833 "2"^^ . _:b429914818 . _:b429914789 . _:b429914790 . _:b7429950 . _:b7430010 "CEACAM1a is highly expressed on epithelia, endothelia, and cells of hematopoietic origin, including macrophages, B cells, and activated T cells (Coutelier et al. 1994; Godfraind et al. >>1995<<; Nakajima et al. 2002)." . _:b429914791 . _:b429914832 "2"^^ . _:b429914784 . _:b429914829 . _:b429914785 . _:b429914786 . _:b429914787 . _:b429914835 "2"^^ . _:b429914796 . _:b429914828 . _:b429914797 . . _:b429914798 . _:b429914799 . _:b429914834 "2"^^ . _:b429914792 . _:b429914831 . _:b429914793 . _:b429914915 . _:b429914794 . _:b429914795 . _:b7430033 "SD (rJHM/SA59) cannot induce hepatitis (Navas and Weiss >>2003<<). Thus, spike alone is unable to dictate organ tropism." . _:b429914845 "2"^^ . _:b429914804 . _:b429914521 . _:b429914805 . . _:b429914830 . _:b429914806 . _:b429914807 . _:b429914844 "2"^^ . _:b429914800 . _:b429914825 . _:b429914801 . _:b429914802 . _:b429914803 . _:b429914847 "2"^^ . _:b429914812 . _:b429914824 . _:b429914813 . _:b429914814 . _:b429914815 . _:b7430188 "Furthermore, the effect of epitope escape mutations on pathogenesis depended on both viral background genes other than the spike and the mouse strain infected (MacNamara et al. 2005a). Thus, epitope escape is unlikely to be a general mechanism that contributes significantly to MHV persistence." . _:b429914846 "2"^^ . _:b7430146 "in the brain, as well as prolonged expression of IFN-\u03B2, whereas A59 infection is characterized predominantly by T cell infiltration into the brain consistent with higher levels of T cell-attracting chemokines (Rempel et al. 2004a, b; Iacono et al. 2006; Scott et al. 2008)." . _:b429914808 . _:b429914827 . _:b429914809 . _:b429914810 . _:b429914811 . _:b429914841 "2"^^ . _:b429914756 . _:b429914826 . _:b429914757 . _:b429914758 . _:b429914759 . _:b429914840 "2"^^ . _:b429914752 . _:b429914837 . _:b429914753 . . _:b429914754 . _:b429914755 . . _:b429914764 . _:b429914843 "2"^^ . . _:b429914765 . _:b429914836 . _:b429914766 . _:b429914767 . _:b429914842 "2"^^ . _:b429914760 . _:b429914839 . _:b429914761 . . _:b429914762 . . _:b429914763 . _:b429914853 "2"^^ . _:b429914772 . _:b429914838 . _:b429914773 . _:b429914774 . _:b429914775 . _:b429914852 "2"^^ . _:b429914768 . _:b429914833 . _:b429914769 . _:b429914770 . _:b429914771 . _:b429914855 "2"^^ . _:b429914780 . _:b429914832 . _:b429914781 . _:b429914782 . _:b429914783 . _:b429914854 "2"^^ . _:b429914776 . _:b429914835 . _:b429914777 . _:b429914778 . _:b429914779 . _:b429914849 "2"^^ . _:b429914724 . _:b429914834 . _:b429914725 . . _:b429914726 . _:b429914727 . _:b429914848 "2"^^ . _:b429914720 . _:b429914845 . _:b7430105 . _:b429914721 . _:b429914722 . _:b429914723 . _:b429914898 . _:b429914732 . _:b429914851 "2"^^ . _:b429914844 . _:b7430128 "In contrast to the induction of type I IFN observed in vivo in the murine CNS, MHV induces type I IFN mRNA very poorly and only at very late times after infection in murine fibroblast cell lines (Roth-Cross et al. 2007, >>2008<<). Thus, it was of interest to determine which CNS cell types produce IFN-\u03B2 in response to MHV infection." . _:b429914733 . . _:b429914734 . _:b429914735 . _:b7430038 . _:b429914850 "2"^^ . _:b429914728 . _:b429914847 . _:b429914729 . _:b429914730 . _:b429914909 . _:b429914731 . _:b429914577 . _:b429914861 "2"^^ . _:b429914740 . _:b429914846 . _:b429914741 . _:b429914742 . _:b429914743 . _:b429914860 "2"^^ . _:b429914736 . _:b429914841 . _:b429914737 . _:b429914738 . _:b429914739 . _:b429914863 "2"^^ . _:b429914748 . _:b429914840 . _:b429914749 . _:b429914750 . _:b429914751 . _:b429914862 "2"^^ . _:b429914744 . _:b429914843 . _:b429914745 . _:b429914746 . _:b429914747 . _:b429914857 "2"^^ . _:b429914692 . _:b429914842 . _:b429914693 . _:b429914775 . _:b429914694 . _:b429914695 . _:b429914856 "2"^^ . _:b429914688 . _:b429914853 . _:b429914689 . _:b429914690 . _:b429914860 . _:b429914691 . _:b429914859 "2"^^ . _:b429914700 . _:b429914852 . _:b429914701 . . _:b429914702 . _:b429914703 . . _:b429914858 "2"^^ . _:b429914696 . _:b429914855 . _:b7430103 . _:b429914697 . _:b429914698 . . _:b429914699 . . _:b429914869 "2"^^ . _:b429914708 . _:b429914854 . _:b429914709 . _:b429914628 . _:b429914710 . _:b429914711 . _:b429914868 "2"^^ . _:b429914704 . _:b429914849 . _:b429914705 . _:b429914706 . _:b429914707 . _:b429914871 "2"^^ . _:b429914716 . . _:b429914848 . _:b429914717 . _:b429914718 . _:b429914719 . _:b429914870 "2"^^ . _:b7430117 "with macro domains may vary among coronavirus groups, as a recent report suggests that the macro domain of group I coronaviruses may differ from that of group III coronaviruses in the ability to bind ADP-ribose (Piotrowski et al. >>2009<<)." . _:b429914712 . _:b429914851 . _:b429914713 . _:b429914714 . _:b429914715 . _:b7430121 _:b7430122 . _:b429914660 . _:b429914865 "2"^^ . _:b7430001 . _:b7430121 _:b7430123 . _:b429914661 . _:b429914850 . _:b7430121 _:b7430124 . _:b429914662 . _:b7430121 _:b7430125 . _:b429914663 . _:b7430121 _:b7430126 . _:b429914656 . _:b429914864 "2"^^ . _:b429914542 . _:b7430121 _:b7430127 . _:b7430047 . _:b429914657 . _:b429914861 . _:b7430121 _:b7430128 . _:b429914658 . _:b7430121 _:b7430129 . _:b429914659 . _:b7430121 _:b7430130 . . _:b429914668 . _:b429914867 "2"^^ . _:b7430121 _:b7430131 . _:b7430046 . _:b429914669 . _:b429914860 . _:b7430121 _:b7430132 . _:b429914670 . _:b7430121 _:b7430133 . _:b429914671 . _:b7430121 _:b7430134 . _:b7430179 . _:b7430026 . _:b429914664 . _:b429914866 "2"^^ . _:b429914710 . _:b7430121 _:b7430135 . _:b429914665 . _:b429914863 . _:b7430121 _:b7430136 . _:b429914666 . _:b7430121 _:b7430137 . _:b429914667 . _:b7430121 _:b7430138 . _:b429914676 . _:b429914877 "2"^^ . _:b7430121 _:b7430139 . _:b429914677 . . _:b429914862 . _:b7430121 _:b7430140 . _:b429914678 . _:b429914810 . . _:b7430121 _:b7430141 . _:b429914679 . . _:b7430121 _:b7430142 . _:b429914672 . _:b429914876 "2"^^ . _:b7430121 _:b7430143 . _:b429914673 . _:b429914857 . _:b429914674 . _:b429914675 . _:b429914855 . _:b429914684 . _:b429914879 "2"^^ . _:b429914856 . _:b429914547 . _:b429914685 . _:b7429923 . _:b429914686 . _:b429914687 . . _:b429914680 . _:b429914878 "2"^^ . _:b429914859 . _:b429914681 . _:b429914682 . _:b429914683 . _:b429914873 "2"^^ . _:b429914628 . _:b429914544 . _:b429914629 . _:b429914858 . _:b429914630 . _:b429914631 . _:b429914872 "2"^^ . _:b429914624 . _:b429914869 . _:b429914625 . . _:b429914626 . _:b429914684 . _:b429914627 . _:b429914875 "2"^^ . _:b429914636 . _:b429914868 . _:b429914637 . _:b429914526 . _:b429914638 . _:b429914639 . _:b429914874 "2"^^ . _:b429914632 . _:b429914871 . _:b429914633 . . _:b429914634 . _:b7429925 "HCoV-OC43 (McIntosh et al. 1967), an etiologic agent of croup known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. >>2003<<; Ksiazek et al. 2003; Peiris et al. 2003; Osterhaus et al. 2004)." . _:b429914635 . _:b429914885 "2"^^ . _:b429914644 . _:b429914870 . _:b429914645 . _:b429914646 . _:b429914647 . _:b429914884 "2"^^ . _:b429914640 . _:b429914865 . _:b429914641 . _:b429914869 . _:b7430148 . _:b429914642 . _:b429914643 . _:b429914887 "2"^^ . _:b429914652 . _:b429914864 . _:b429914653 . _:b429914654 . _:b429914655 . _:b429914886 "2"^^ . _:b429914648 . _:b429914867 . _:b429914649 . _:b429914650 . _:b429914651 . . _:b429914881 "2"^^ . _:b429914866 . . _:b7430155 . _:b429914880 "2"^^ . _:b429914877 . . _:b429914883 "2"^^ . _:b7430154 "In contrast, macrophage chemoattractant expression is elevated during rA59/SJHM infection but not during rJHM/SA59 infection, suggesting an influence by the S gene (Iacono et al. 2006; Rempel et al. 2004a; Scott et al. 2008) consistent with the extensive macrophage infiltration observed in response to viruses expressing the JHM." . _:b429914876 . . . _:b429914882 "2"^^ . _:b429914879 . _:b429914893 "2"^^ . _:b429914878 . _:b7430050 . _:b429914892 "2"^^ . . _:b429914873 . _:b7430156 . _:b429914895 "2"^^ . _:b429914872 . _:b429914663 . _:b429914894 "2"^^ . _:b429914875 . . _:b429914889 "2"^^ . _:b429914874 . . _:b429914888 "2"^^ . _:b7430067 "it had long been speculated that HE may play a role in acute and/or chronic MHV disease, either as a determinant of organ and/or cellular tropism (Yokomori et al. 1992, 1993, 1995) or to aid in spread of the virus (Kienzle et al. >>1990<<). Consistent with this hypothesis, some of the highly neurovirulent JHM isolates express an HE protein while HE is not expressed by the tissue culture-adapted and weakly neurovirulent A59 strain (Shieh et al. 1989)." . _:b7430023 _:b7430120 . _:b429914891 "2"^^ . . _:b429914890 "2"^^ . _:b429914832 . _:b7430023 _:b7430112 . . _:b429914532 . _:b7430023 _:b7430113 . _:b7430023 _:b7430114 . _:b429914901 "2"^^ . _:b7430023 _:b7430115 . _:b429914731 . _:b7430023 _:b7430116 . _:b7430023 _:b7430117 . _:b7430023 _:b7430118 . _:b429914900 "2"^^ . _:b7430023 _:b7430119 . _:b7430023 _:b7430104 . _:b7430023 _:b7430105 . _:b7430023 _:b7430106 . _:b429914903 "2"^^ . . _:b7430023 _:b7430107 . _:b7430023 _:b7430108 . _:b7430181 . _:b429914525 . _:b7430023 _:b7430109 . _:b7430023 _:b7430110 . _:b7430182 . _:b429914902 "2"^^ . _:b7430023 _:b7430111 . _:b429914693 . _:b7430023 _:b7430096 . _:b7430023 _:b7430097 . _:b7430023 _:b7430098 . _:b429914897 "2"^^ . _:b7430023 _:b7430099 . . _:b7430023 _:b7430100 . _:b7430023 _:b7430101 . _:b7430023 _:b7430102 . _:b429914896 "2"^^ . _:b7430023 _:b7430103 . _:b429914755 . _:b7430023 _:b7430088 . _:b7430023 _:b7430089 . _:b7430023 _:b7430090 . _:b429914899 "2"^^ . _:b7430023 _:b7430091 . _:b7430023 _:b7430092 . _:b7430023 _:b7430093 . . . _:b7430023 _:b7430094 . _:b429914898 "2"^^ . _:b429914508 . _:b7430023 _:b7430095 . _:b7430023 _:b7430080 . _:b7429968 . _:b7430023 _:b7430081 . _:b7430023 _:b7430082 . _:b429914909 "2"^^ . _:b7430023 _:b7430083 . _:b7430023 _:b7430084 . _:b7430023 _:b7430085 . _:b7430023 _:b7430086 . _:b429914908 "2"^^ . _:b7430023 _:b7430087 . _:b7430023 _:b7430072 . _:b429914501 . _:b7430023 _:b7430073 . _:b7430023 _:b7430074 . _:b429914911 "2"^^ . _:b7430023 _:b7430075 . _:b7430023 _:b7430076 . . _:b7430023 _:b7430077 . _:b7430023 _:b7430078 . _:b429914910 "2"^^ . _:b7430023 _:b7430079 . _:b429914579 . _:b7430023 _:b7430064 . _:b7430023 _:b7430065 . _:b7430023 _:b7430066 . _:b429914825 . _:b429914905 "2"^^ . _:b429914723 . _:b7430023 _:b7430067 . _:b7430023 _:b7430068 . _:b7430023 _:b7430069 . _:b7430023 _:b7430070 . _:b429914904 "2"^^ . _:b7430023 _:b7430071 . _:b7430023 _:b7430056 . _:b7430008 . . _:b7430023 _:b7430057 . _:b429914690 . _:b7430023 _:b7430058 . _:b429914907 "2"^^ . _:b7430023 _:b7430059 . _:b7430023 _:b7430060 . _:b429914727 . . _:b7430028 "Characterization of isogenic recombinant MHV strains differing only in spike has definitively demonstrated the important role of spike in determining neurovirulence during infection in the mouse (Phillips et al. 1999, >>2002<<; Navas and Weiss 2003; Iacono et al. 2006)." . _:b7430023 _:b7430061 . _:b7430023 _:b7430062 . _:b429914906 "2"^^ . _:b7430023 _:b7430063 . _:b7430023 _:b7430048 . _:b7430010 . _:b7430023 _:b7430049 . . . _:b429914703 . _:b7429993 . _:b429914917 "2"^^ . _:b7429994 "CD8 T cells, which play a dominant role in controlling virus replication, are most numerous in the brain at day\u00A07 post-infection, coinciding with viral clearance (Williamson et al. >>1991<<). However, despite clearance of infectious virus, viral RNA persists in the CNS and demyelination, largely immune-mediated, becomes evident around 4\u00A0weeks post-infection (Lavi et al. 1984a, b). A notable exception to this disease course" . _:b7430023 _:b7430050 . _:b7430023 _:b7430051 . _:b7430023 _:b7430052 . _:b7430023 _:b7430053 . _:b7430023 _:b7430054 . _:b429914916 "2"^^ . _:b7430023 _:b7430055 . _:b429914524 . _:b7430023 _:b7430040 . . _:b429914852 . _:b7430023 _:b7430041 . _:b7430023 _:b7430042 . _:b429914919 "2"^^ . . _:b7430023 _:b7430043 . _:b7430023 _:b7430044 . _:b7430176 "clearance, whereas cells transferred into CD4-depleted mice were unable to effectively clear virus from the CNS, suggesting that the ability of virus-specific CD8 T cells to control infection depends on CD4 T cells (Stohlman et al. >>1998<<). Furthermore, CD4 T cells have been shown to be required for production of MHV-specific antibodies during infection with the JHM-DS variant (Williamson and Stohlman 1990)." . . _:b7430023 _:b7430045 . _:b7430023 _:b7430046 . _:b429914918 "2"^^ . _:b7430023 _:b7430047 . _:b7430023 _:b7430032 . _:b7430023 _:b7430033 . _:b7430170 "SD, perhaps due, at least in part, to the effects of antiviral CD8 T cells (Phillips et al. >>1999<<; Iacono et al. 2006)." . _:b7430023 _:b7430034 . _:b429914913 "2"^^ . _:b7430023 _:b7430035 . _:b7430023 _:b7430036 . _:b7430023 _:b7430037 . _:b7430023 _:b7430038 . _:b429914912 "2"^^ . _:b7430023 _:b7430039 . _:b429914596 . _:b7430023 _:b7430024 . _:b7430023 _:b7430025 . _:b7430089 . _:b429914564 . _:b429914592 . _:b7430023 _:b7430026 . _:b429914915 "2"^^ . _:b7430023 _:b7430027 . _:b7430023 _:b7430028 . _:b7430023 _:b7430029 . _:b7430023 _:b7430030 . _:b429914914 "2"^^ . _:b7430023 _:b7430031 . . . _:b429914921 "2"^^ . _:b429914645 . _:b429914920 "2"^^ . . . . _:b7429920 "along with toroviruses and roniviruses, are members of the order Nidovirales (\u201Cnido\u201D meaning \u201Cnest\u201D), so named because of the nested set of subgenomic RNAs generated during the life cycle of these viruses (Gorbalenya et al. >>2006<<). Coronaviruses are typically categorized into three groups based on antigenic similarity, with viruses in all groups being able to infect a range of different host species." . . . _:b7430169 . _:b7430036 "Furthermore, this Gly substitution at position 310 is associated with the ability to spread cell-to-cell in a CEACAM1a-independent manner (Ontiveros et al. >>2003<<). Characterization of viruses in which the RBDs of A59 and JHM.SD were exchanged further demonstrated that the ability to carry out CEACAM1a-independent spread required both the RBD and the rest of the spike to be derived from JHM (Tsai" . . . . _:b7429954 . _:b429914916 . _:b429914917 . _:b429914918 . _:b7430049 "SD, such as V5A13.1 (Fazakerley et al. 1992), are associated with single site mutations and/or deletions within the HVR (Dalziel et al. >>1986<<; Gallagher et al. 1990; Phillips et al. 2001)." . _:b429914919 . _:b429914912 . _:b429914913 . _:b429914914 . _:b429914915 . _:b429914920 . _:b7430074 "demonstrated by comparison of isogenic recombinant viruses expressing a wild-type HE protein, a full-length HE protein in which the esterase activity had been eliminated, and a virus expressing a truncated HE polypeptide (Kazi et al. >>2005<<). The viruses that expressed full-length HE polypeptides (with or without a functional esterase activity) were more virulent when inoculated intracranially into mice and spread more extensively in the CNS compared to viruses expressing a" . _:b429914921 . . _:b7430108 "Together, the putative CPD domain and the ADRP domain could potentially participate in a pathway of nucleotide processing (Gorbalenya et al. >>1991<<; Snijder et al. 2003) in which the CPD would convert ADP-ribose-1\u2033,2\u2033-cyclic phosphate into ADP-ribose 1\u2033 phosphate and the ADRP would convert the product of the CPD, ADP-ribose 1\u2033 phosphate, into ADP-ribose and inorganic phosphate" . . . . _:b7429969 . _:b7430136 "the numbers and types of infiltrating cells and the chemokines secreted are dependent on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. 2001; Glass et al. 2002; Rempel et al. 2004b; Bergmann et al. 2006; Iacono et al. 2006; Savarin et al. 2008; Scott et al. 2008)." . . . _:b429914516 . _:b429914884 . _:b429914885 . _:b429914513 . _:b429914886 . _:b429914887 . _:b429914880 . _:b429914792 . _:b429914881 . _:b429914882 . _:b429914883 . . _:b429914892 . . _:b429914893 . _:b429914858 . _:b429914894 . _:b429914895 . _:b429914888 . _:b429914891 . _:b429914889 . _:b429914890 . _:b429914891 . . _:b429914900 . . _:b429914901 . _:b429914902 . _:b429914903 . _:b429914896 . _:b429914897 . _:b7429938 . _:b429914898 . _:b429914899 . _:b429914908 . _:b429914909 . _:b429914910 . . _:b429914911 . _:b429914904 . _:b429914905 . _:b429914906 . _:b7429975 "Leslie Weiner later serially passaged this virus multiple times through mouse brains (Weiner >>1973<<; Weiner et al. 1973)." . _:b429914907 . _:b429914573 . . . _:b429914873 . . _:b7430006 . _:b7429967 "remains elevated during late disease, and the observation that antibody depletion of either CXCL10 or CCL5 results in reduced levels of demyelination suggests an important role for these chemokines (Liu et al. 2001; Glass et al. >>2002<<, 2004). Chronic activation of astrocytes during persistent infection contributes to demyelination via the secretion of macrophage and T cell chemoattractants, and it has been suggested that additional secretion of TNF-\u03B1, IL-1\u03B2, IL-6, and" . _:b429914769 . . . _:b7430017 "The recent generation of a knockout mouse deficient in ceacam1a (ceacam1a\u2212/\u2212) by targeted deletion of the exon encoding the N-terminal domain has made it possible to evaluate MHV infection in the absence of CEACAM1a (Hemmila et al. >>2004<<). Interestingly, two neurotropic MHV strains, A59 and JHM.SD, differ in their ability to cause CNS disease in these mice following intracranial inoculation." . . _:b7430071 "There were early studies both supporting and arguing against a role for HE in MHV pathogenesis (Taguchi et al. 1986; LaMonica et al. 1991; Yokomori et al. >>1992<<, 1993, 1995)." . _:b429914704 . _:b7430035 "4; Frana et al. 1985; Luytjes et al. >>1988<<). Spike is expressed on the virion membrane as a trimer in which the S1 subunits form a globular head structure and the S2 subunits form a transmembrane stalk (Fig." . . . _:b7430091 . _:b429914806 . . . . _:b7429930 "While enteric strains are typically responsible for MHV outbreaks in housed rodent colonies (Homberger et al. >>1998<<), the most frequently studied are the neurotropic strains due to their ability to induce acute encephalomyelitis with or without chronic demyelination." . . _:b7430117 . . . _:b429914696 . _:b7429950 "With the exception of the suckling mouse model (Pewe et al. >>1999<<), demyelination occurs in the absence of detectable infectious virus." . . _:b7430113 . _:b7429974 . _:b7429976 . . . . _:b429914843 . _:b7430113 "While CPD activity has not yet been demonstrated for the MHV ns2 protein, the ADRPs of several coronaviruses (including SARS-CoV, HCoV-229E, and porcine TGEV) were demonstrated to have phosphatase activity (Putics et al. 2005, 2006a). In addition, the ADRP also has binding activity to mono- and poly-ADP-ribose, implying that it may participate in ribosylation of host cell proteins, which may promote apoptosis or necrosis (Egloff et al. 2006)." . _:b7429975 . _:b7429994 . _:b7430078 "The coronavirus E protein is an integral membrane protein (Yu et al. 1994) that plays an important role in viral assembly (Vennema et al. >>1996<<). Surprisingly, E is not an essential protein; however, a recombinant MHV lacking E expression replicates very inefficiently, consistent with the important role of E in production of infectious virus (Kuo and Masters 2003)." . _:b429914588 . . _:b7430160 . _:b7430000 "CEACAM1a is a multifunctional protein shown to play diverse roles in a variety of cellular processes, including intercellular adhesion, tumor suppression, angiogenesis, and immune cell signaling (Gray-Owen and Blumberg >>2006<<; Kuespert et al. 2006)." . _:b429914486 . . _:b429914905 . . _:b7429999 "receptor for MHV has been identified as CEACAM1a (also referred to as mmCGM1, BGP1a, and CD66a) belonging to the carcinoembryonic antigen family of cell adhesion molecules within the immunoglobulin superfamily (Williams et al. 1990, >>1991<<). CEACAM1a is a multifunctional protein shown to play diverse roles in a variety of cellular processes, including intercellular adhesion, tumor suppression, angiogenesis, and immune cell signaling (Gray-Owen and Blumberg 2006; Kuespert et" . _:b7430014 "microglia serve as the initial target of infection and that virus subsequently spreads to other CNS cell types in a CEACAM1a-independent manner; a soluble receptor-resistant mutant of cl-2 known as srr7 (Matsuyama et al. >>2001<<) cannot spread without CEACAM1a and is thus restricted to microglia in mixed neural cultures (Nakagaki and Taguchi 2005)." . _:b7430082 "the E protein of SARS-CoV may disrupt ion homeostasis in the host cell and that pro-apoptotic effects attributed to E (An et al. 1999) could result from membrane depolarization resulting from such ionic disturbances (Pervushin et al. >>2009<<)." . _:b7430177 . _:b429914632 . . _:b7430165 "viral replication and spread throughout the brain and spinal cord as well as demyelination compared to control mice; thus, enhancing the host CD8 T cell response was protective against A59-induced CNS disease (MacNamara et al. 2005b)." . _:b7430000 . _:b7429952 . _:b7430061 . . . _:b429914660 . . _:b7429919 . _:b429914844 . _:b7430133 "by the observation that IFNAR expression in the glomerular layer of the olfactory bulb is essential to prevent vesicular stomatitis virus from replicating and spreading in the CNS following intranasal inoculation (Detje et al. >>2009<<). We are currently investigating the role of type I IFN signaling in protection during MHV infection in specific CNS cell types." . _:b429914828 . . _:b429914772 . _:b429914695 . _:b429914477 . _:b7429924 . _:b429914476 . _:b7429929 . _:b7430054 "One of these substitutions alone, L1114R, is sufficient to confer neuroattenuation and restriction to the olfactory bulbs (Gallagher et al. 1991; Tsai et al. 2003b; Pearce et al. 1994)." . _:b7429925 . _:b429914479 . _:b7429926 . _:b429914562 . _:b429914478 . _:b7429931 . _:b429914671 . _:b7429927 . _:b7429920 . _:b7430098 "Nevertheless, it is clear that the nsp1 proteins of MHV and SARS-CoV are both virulence factors (Frieman et al. >>2008<<)." . _:b7430137 . _:b7429921 . _:b429914475 . _:b7429922 . _:b7429923 . _:b429914485 . . _:b7429932 . _:b7430188 . _:b429914484 . _:b7429933 . _:b429914487 . _:b7429934 . _:b7430179 "IA strain was shown to prevent mortality in C57BL/6 mice while having no effect on disease severity in BALB/c mice, a strain in which the M133 epitope is not recognized (Anghelina et al. >>2006<<). Thus, while T lymphocytes are required for effective clearance of infectious MHV from the CNS, their effects can be both protective and pathogenic to the host." . _:b429914486 . _:b7429935 . _:b429914481 . _:b429914580 . _:b7429928 . _:b7430060 "These substitutions are associated with an inability to induce CEACAM1a-independent cell-to-cell fusion as well as neuroattenuation (Matsuyama and Taguchi 2002a, b; Taguchi and Matsuyama >>2002<<). Interestingly, viruses expressing the JHM spike with a L1114F substitution have lost their tropism for neurons while the OBLV60 mutant, expressing a spike carrying the L1114R substitution, can readily infect neurons of the olfactory" . _:b429914480 . _:b7429929 . _:b429914545 . _:b429914483 . . _:b7429930 . _:b429914576 . _:b429914482 . _:b7429931 . _:b429914868 . _:b429914493 . _:b7429940 . _:b429914492 . _:b7429941 . . _:b7430024 . _:b429914495 . _:b7429942 . _:b7430185 . . _:b429914494 . _:b7429943 . _:b429914713 . _:b429914489 . _:b7429936 . _:b7430123 "by several recent reports of the high mortality following MHV infection that were carried out in the absence of IFN signaling in type I interferon receptor deficient (IFNAR\u2212/\u2212) mice (Cervantes-Barragan et al. 2007; Ireland et al. >>2008<<; Roth-Cross et al. 2008). IFNAR\u2212/\u2212 mice inoculated intracranially with low doses of the neurotropic MHV strains A59 and JHM." . _:b429914488 . _:b7429937 . . . _:b429914491 . _:b7429938 . _:b429914490 . _:b7429939 . _:b7430085 "N plays an important role in enhancing efficiency of transcription (Compton et al. >>1987<<) and significantly enhances recovery of infectious virus from cells transfected with genome length synthetic RNA (Grossoehme et al. 2009)." . _:b429914501 . _:b7429948 . . _:b429914809 . _:b429914500 . _:b7429949 . . _:b429914503 . _:b7429950 . _:b429914502 . _:b7429951 . . _:b429914497 . _:b7430178 "in viral clearance; while viral replication was initially controlled by both IFN-\u03B3- and perforin-deficient CD4 T cell populations, only those cells competent to express IFN-\u03B3 were able to maintain prolonged control (Stohlman et al. >>2008<<). Interestingly, CD4 T cells have also been shown to play a pathogenic role during MHV infection." . _:b7429944 . _:b7429944 . _:b7430086 . _:b429914496 . _:b7429945 . _:b429914499 . _:b7429946 . . _:b429914498 . _:b7429947 . _:b7430053 "One of these substitutions alone, L1114R, is sufficient to confer neuroattenuation and restriction to the olfactory bulbs (Gallagher et al. >>1991<<; Tsai et al. 2003b; Pearce et al. 1994)." . _:b429914625 . _:b429914687 . . _:b429914509 . . _:b7429956 . . _:b429914508 . _:b429914910 . . _:b7429957 . _:b429914511 . _:b7429958 . _:b7430161 . _:b429914510 . _:b7429959 . . _:b429914709 . _:b429914505 . _:b7429952 . _:b429914500 . . _:b429914504 . _:b7429953 . _:b429914764 . _:b7430151 "The spike gene has been demonstrated to be a determinant of neurovirulence and to influence macrophage, but not T cell, infiltration into the brain (Phillips et al. 1999, 2002; Rempel et al. 2004a; Iacono et al. 2006). Analysis of recombinant chimeric A59/JHM viruses was carried out to determine if the spike and/or background genes determined these differences in inflammatory cell infiltrates and chemokine expression." . _:b429914507 . _:b7429954 . _:b429914506 . _:b7429955 . _:b7430054 . . . _:b429914517 . _:b7429964 . . _:b429914516 . . _:b7429965 . _:b429914584 . . _:b429914519 . _:b7429966 . . . _:b429914518 . _:b7429967 . _:b429914896 . _:b429914513 . _:b7429960 . _:b429914512 . _:b7429961 . _:b429914556 . . _:b429914515 . _:b7429962 . . . _:b429914514 . _:b429914619 . _:b7429963 . . _:b429914525 . _:b7429972 . _:b429914524 . _:b7429973 . . _:b429914527 . _:b7429974 . _:b429914609 . _:b7430133 . _:b429914526 . _:b7429975 . . _:b7430093 "However, this effect occurs via induction of fibrinogen-like protein 2 (fgl2; Parr et al. 1995; Ning et al. 1999, >>2005<<) by the N proteins of hepatotropic MHV-3 and A59 strains, and there is no evidence to suggest that fgl2 plays a role in CNS pathogenesis." . _:b429914521 . _:b7429968 . . . _:b429914520 . _:b7429969 . _:b429914523 . _:b7429970 . _:b429914522 . _:b7429971 . _:b429914533 . . _:b7429980 . . . _:b429914532 . _:b7429981 . _:b7430157 "combined immunodeficient (SCID), recombination-activating gene (RAG)-deficient, or sublethally irradiated wild-type mice have demonstrated that the host adaptive immune response plays a pivotal role in viral clearance (Wang et al. >>1990<<; Houtman and Fleming 1996; Wu and Perlman 1999; Matthews et al. 2002)." . _:b429914535 . _:b7429982 . . . _:b7430194 "in oligodendrocytes, while viral recrudescence in B cell-deficient mice was observed in both oligodendrocytes and astrocytes, suggesting an additional level of protection provided by B cells during persistence (Ramakrishna et al. >>2002<<). Furthermore, the numbers of antibody-secreting cells were shown to remain stable during persistence (Tschen et al. 2002)." . _:b429914534 . _:b7429983 . . _:b429914529 . _:b7429976 . _:b429914821 . _:b7430022 . _:b429914528 . _:b7429977 . _:b429914773 . _:b429914531 . _:b7429978 . . . _:b429914530 . . _:b7429979 . . _:b429914541 . _:b7429988 . _:b429914540 . _:b7429989 . _:b7429981 . _:b7430076 . _:b429914543 . _:b7429990 . _:b429914533 . _:b429914542 . _:b7429991 . . _:b429914537 . _:b7429984 . _:b429914644 . _:b429914808 . . . . _:b429914536 . _:b7429985 . . . _:b429914539 . _:b7429986 . _:b429914606 . _:b429914538 . _:b7429987 . . _:b429914549 . _:b7429996 . _:b429914548 . _:b7430150 . _:b7430103 "Indeed, several studies have demonstrated that the PLP of SARS-CoV inhibits both the IRF3 and NF-\u03BAB pathways (Devaraj et al. 2007; Frieman et al. >>2009<<). However, there are conflicting data regarding the role of MHV PLP-2 as a type I IFN antagonist (Zheng et al. 2008; Frieman et al. 2009), and it is possible that the MHV- and SARS-CoV-encoded proteases may differ in this activity." . _:b7429997 . _:b429914551 . _:b7429998 . _:b7430140 . _:b429914550 . _:b7429999 . _:b429914783 . _:b429914545 . _:b7429992 . _:b7429965 "The persistence of viral RNA, both genome and mRNA (unpublished data), and likely low levels of viral antigen within the CNS are responsible for the maintenance of T cells in the CNS during chronic disease (Ramakrishna et al. 2004, >>2006<<). Furthermore, expression of CXCL10 (IP-10) and CCL5 (RANTES), which attract T cells and macrophages respectively, remains elevated during late disease, and the observation that antibody depletion of either CXCL10 or CCL5 results in" . _:b7430058 . _:b429914544 . _:b7429993 . _:b429914717 . _:b429914547 . _:b7429994 . . _:b429914658 . _:b429914546 . _:b7429995 . . _:b429914557 . _:b7430004 . _:b429914554 . _:b429914556 . _:b7430005 . _:b429914725 . _:b429914559 . _:b7430006 . _:b429914558 . _:b7430007 . _:b429914757 . _:b429914553 . _:b7430000 . . _:b429914488 . _:b429914733 . _:b429914552 . _:b7430001 . _:b7430125 . _:b429914793 . _:b429914555 . _:b7430002 . _:b7430124 . _:b429914554 . . _:b7430003 . _:b429914722 . _:b429914565 . _:b7430012 . _:b429914564 . _:b7430013 . _:b429914567 . _:b7430014 . _:b429914559 . _:b429914566 . _:b7430015 . _:b429914583 . _:b429914561 . _:b7430119 . _:b7430008 . _:b7429945 . _:b429914560 . _:b7429934 . _:b7430009 . _:b429914563 . _:b7429972 . _:b7430010 . _:b429914562 . _:b7430011 . _:b7429969 "has been suggested that additional secretion of TNF-\u03B1, IL-1\u03B2, IL-6, and type 2 nitric oxide synthesis (iNOS) by astrocytes may directly contribute to the dysregulation of oligodendrocyte function and resulting myelin loss (Sun et al. >>1995<<; Grzybicki et al. 1997)." . _:b429914573 . _:b7430020 . _:b429914572 . _:b7430021 . _:b7430192 . _:b7430057 "substitution has also been identified in the spike of the 2.2-V-1 glial-tropic variant of JHM-DL (Wang et al. 1992) and in the spike of the highly attenuated soluble receptor-resistant mutant srr7 derived from JHM cl-2 (Saeki et al. >>1997<<, 1998). These substitutions are associated with an inability to induce CEACAM1a-independent cell-to-cell fusion as well as neuroattenuation (Matsuyama and Taguchi 2002a, b; Taguchi and Matsuyama 2002)." . _:b429914575 . . _:b7430022 . _:b429914574 . . _:b7430023 . _:b429914569 . _:b7430016 . _:b429914568 . _:b7429962 "Thus, while either CD4 or CD8 T cells are sufficient to promote demyelination, neither cell type is essential (Wu et al. 2000; Matthews et al. >>2002<<). Infection of B cell-deficient mice similarly confirmed that this cell type is also not required for the development of demyelination (Matthews et al. 2002)." . _:b7429927 . _:b7430017 . _:b7430077 "The coronavirus E protein is an integral membrane protein (Yu et al. >>1994<<) that plays an important role in viral assembly (Vennema et al. 1996)." . _:b429914571 . _:b7430018 . _:b429914889 . _:b429914570 . _:b7430019 . _:b429914581 . _:b7430028 . _:b429914580 . _:b7430029 . _:b429914569 . _:b429914583 . _:b429914590 . _:b7430030 . _:b429914582 . . _:b7430031 . _:b429914577 . _:b7430018 "SD to cause disease in these mice was mapped to the spike gene (Hemmila et al. >>2004<<; Miura et al. 2008)." . _:b7430024 . _:b429914576 . . _:b7430025 . _:b7430121 _:b7430144 . _:b7430121 _:b7430145 . _:b429914579 . . _:b7430026 . _:b7430121 _:b7430146 . _:b7430121 _:b7430147 . _:b7430121 _:b7430148 . _:b7430132 . _:b7429963 "Infection of B cell-deficient mice similarly confirmed that this cell type is also not required for the development of demyelination (Matthews et al. >>2002<<)." . _:b429914578 . _:b7430121 _:b7430149 . _:b7430121 _:b7430150 . _:b7430027 . _:b429914682 . . _:b7430121 _:b7430151 . . _:b7430121 _:b7430152 . _:b7430121 _:b7430153 . _:b429914589 . _:b7430121 _:b7430154 . _:b7430036 . _:b7430121 _:b7430155 . _:b7430121 _:b7430156 . _:b7430121 _:b7430157 . _:b429914588 . _:b7430121 _:b7430158 . _:b7430037 . _:b7430121 _:b7430159 . _:b7430121 _:b7430160 . _:b7430129 . _:b429914503 . _:b429914591 . _:b7430121 _:b7430161 . _:b429914506 . _:b7430121 _:b7430162 . _:b7430038 . _:b429914677 . _:b429914706 . _:b7430121 _:b7430163 . _:b7430121 _:b7430164 . _:b7430128 . _:b7430121 _:b7430165 . _:b429914590 . _:b429914490 . _:b7430121 _:b7430166 . _:b7430039 . _:b7430121 _:b7430167 . _:b7430121 _:b7430168 . _:b7430121 _:b7430169 . _:b429914585 . _:b7430121 _:b7430170 . _:b7430032 . _:b7430121 _:b7430171 . _:b7430121 _:b7430172 . _:b7430121 _:b7430173 . _:b429914900 . _:b429914584 . _:b7430121 _:b7430174 . _:b7430156 "Interestingly, induction of significant levels of neutrophils as well as the neutrophil chemoattractant CXCL2 (MIP-2) required both spike and background genes from JHM.SD (Scott et al. >>2008<<)." . _:b7430033 . . _:b7430121 _:b7430175 . _:b7430121 _:b7430176 . _:b7430121 _:b7430177 . _:b429914587 . _:b7430121 _:b7430178 . _:b7430034 . _:b7430121 _:b7430179 . _:b7430121 _:b7430180 . _:b7430121 _:b7430181 . _:b429914586 . _:b7430121 _:b7430182 . _:b7430035 . _:b7430121 _:b7430183 . _:b7430121 _:b7430184 . _:b7430121 _:b7430185 . _:b429914597 . _:b7430121 _:b7430186 . _:b7430044 . _:b7430121 _:b7430187 . _:b7430121 _:b7430188 . _:b7430121 _:b7430189 . _:b429914596 . _:b7430121 _:b7430190 . _:b7430045 . _:b7430121 _:b7430191 . _:b7430121 _:b7430192 . _:b7430121 _:b7430193 . _:b429914599 . _:b7430121 _:b7430194 . _:b7430046 . _:b7430121 _:b7430195 . _:b7429992 "Viral titers typically peak at day\u00A05 post-infection and then begin to decline (Leparc-Goffart et al. >>1998<<), with infectious virus becoming undetectable by approximately 2\u00A0weeks post-infection (Matthews et al. 2001)." . _:b429914598 . _:b7430047 . . _:b429914593 . _:b7430040 . _:b429914592 . _:b7430041 . _:b429914595 . _:b7430042 . _:b429914594 . . _:b7430043 . _:b7429988 . _:b429914605 . _:b7430052 . _:b7430148 "expression of IFN-\u03B2, whereas A59 infection is characterized predominantly by T cell infiltration into the brain consistent with higher levels of T cell-attracting chemokines (Rempel et al. 2004a, b; Iacono et al. 2006; Scott et al. >>2008<<)." . _:b7429989 . _:b429914604 . _:b7430053 . _:b429914607 . _:b7430054 . _:b429914606 . _:b429914676 . _:b7430055 . _:b429914497 . _:b429914601 . _:b7430048 . _:b429914600 . _:b7430070 . _:b7430049 . _:b429914603 . _:b7430050 . _:b7430006 "tyrosine residues within immunoreceptor tyrosine-based inhibitory motifs that have been shown to participate in protein\u2013protein interactions and downstream signaling cascades in a variety of cell types, including T cells (Chen et al. >>2008<<) and dendritic cells (Kammerer et al. 2001). Thus, it is tempting to speculate that MHV binding to long-tailed isoforms may trigger or modulate intracellular signaling pathways in ways that virus binding to short-tailed isoforms may not." . _:b7429955 "MHV-induced demyelination is characterized by inflammatory infiltrates consisting of lymphocytes and lipid-containing macrophages (Stohlman and Weiner 1981; Lavi et al. 1986a, b; Wu and Perlman 1999)." . _:b429914602 . _:b7430051 . _:b429914604 . _:b7429996 . _:b7429997 "receptor and tropism" . _:b7430094 . _:b429914613 . _:b7430060 . _:b429914612 . _:b7430061 . _:b429914874 . _:b7429990 "IANeurons, glial cellsS310G; CEACAM1-independent spreadOntiveros et al. (2003)A59Neuroattenuated; mild encephalitis; subacute demyelination; hepatitisNeurons, glial cellsHVR deletion (52 aa); CEACAM1-dependent spreadLavi et al. (1984a, b) Fig." . . _:b429914615 . _:b7430062 . _:b429914614 . _:b429914770 . _:b429914540 . _:b7430063 . _:b429914609 . _:b7430056 . _:b429914608 . _:b7430057 . _:b429914553 . _:b429914902 . . _:b429914611 . _:b7430058 . _:b429914726 . _:b429914610 . _:b7430059 . _:b429914621 . _:b7430068 . . _:b429914620 . _:b7430069 . _:b429914623 . . _:b7430070 . _:b7430024 "Paul Masters (Koetzner et al. >>1992<<; Kuo et al. 2000), allows the exchange of viral genes and insertion of site-directed targeted mutations within the 3\u2032 one third of the genome encoding the viral structural genes (Fig." . . _:b429914622 . _:b7430071 . . _:b429914857 . _:b7430125 "increased levels of infectious virus in the brain and spinal cord (and in the case of A59, the liver) of infected IFNAR\u2212/\u2212 mice, as well as spread to other organs not usually affected, compared to wild-type mice (Roth-Cross et al. >>2008<<). Following intracranial inoculation of IFNAR\u2212/\u2212 mice with the glial-tropic JHM variant 2.2-V-1, the virus was able to spread more extensively among glial cell types compared with wild-type mice as well as to neurons, a cell type not" . _:b429914617 . _:b7430064 . _:b429914616 . _:b7430065 . _:b429914875 . _:b7430143 "antigen through the brain accompanied by greater levels of infiltrating neutrophils and macrophages, as well as increased cellular destruction, compared to the weakly neurovirulent A59 strain (Rempel et al. 2004a, b; Iacono et al. >>2006<<). While infiltrating neutrophils had a protective effect for animals infected with the attenuated, glial-tropic JHM variant 2.2-V-1 (Zhou et al. 2003), neutrophil depletion studies using the highly neurovirulent JHM." . _:b429914619 . _:b7430034 . _:b7430066 . _:b429914618 . _:b7430067 . _:b7430122 "This role is supported by several recent reports of the high mortality following MHV infection that were carried out in the absence of IFN signaling in type I interferon receptor deficient (IFNAR\u2212/\u2212) mice (Cervantes-Barragan et al. >>2007<<; Ireland et al. 2008; Roth-Cross et al. 2008). IFNAR\u2212/\u2212 mice inoculated intracranially with low doses of the neurotropic MHV strains A59 and JHM." . _:b7430076 . . _:b7430163 . . _:b7430077 . . _:b7430078 . . _:b7430079 . . _:b7430072 . _:b7430073 . _:b7429999 . _:b7430074 . _:b429914614 . _:b7430075 . _:b7430191 . _:b7430084 . _:b429914893 . _:b7430085 . . _:b7430037 "SD were exchanged further demonstrated that the ability to carry out CEACAM1a-independent spread required both the RBD and the rest of the spike to be derived from JHM (Tsai et al. 2003a). Interestingly, a single amino acid substitution, Q159L, within the RBD eliminates the ability of A59 to infect the liver while having no measurable effect on neurovirulence (Leparc-Goffart et al. 1997; Leparc-Goffart et al. 1998)." . _:b7430086 . _:b7430035 . _:b7430087 . _:b429914807 . _:b7430080 . _:b7429982 "persistently infected OBL21A cells)NeuroattenuatedOlfactory bulb neuronsL1114R; CEACAM1-dependent spreadGallagher et al. (1991), Pearce et al. (1994)JHM-DLHighly lethalNeurons, glial cellsLeu1114Stohlman et al. (1982), Wang et al. (>>1992<<)2.2-V-1 (mAb escape mutant of JHM-DL)Neuroattenuated; subacute demyelinationGlial cells, primarily oligodendrocytesL1114F; CEACAM1-dependent spreadFleming et al. (1986), Wang et al. (1992)JHM cl-2Highly lethalNeurons, glial cellsGly310;" . _:b429914485 . . _:b7430081 . _:b429914867 . _:b429914804 . _:b7430082 . . _:b7430083 . _:b7429949 . _:b7430092 . _:b7430093 . _:b7430069 "There were early studies both supporting and arguing against a role for HE in MHV pathogenesis (Taguchi et al. >>1986<<; LaMonica et al. 1991; Yokomori et al. 1992, 1993, 1995)." . . _:b7430094 . _:b429914754 . "PMC0" . _:b7430095 . _:b429914880 . _:b7430088 . _:b429914797 . _:b7430089 . _:b7429928 "known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. 2003; Ksiazek et al. 2003; Peiris et al. 2003; Osterhaus et al. >>2004<<). While coronaviruses are commonly regarded as being highly species-specific, the recent emergence of SARS-CoV in humans has brought renewed awareness to the potential for cross-species virus transmission from animal reservoirs." . _:b7430087 . . _:b7429964 . _:b7430090 . _:b7430091 . _:b7430036 . . _:b7430100 . . _:b7430101 . _:b7430102 . . _:b7430103 . _:b429914647 . _:b7430096 . _:b7430049 . . _:b7430097 . _:b7430098 . . _:b7430099 . _:b429914691 . _:b7430108 . _:b7430109 . _:b7429930 . _:b7430110 . _:b429914659 . _:b7430111 . _:b7430040 . _:b7430104 . _:b7430041 . . _:b429914887 . _:b7430105 . _:b7430059 "These substitutions are associated with an inability to induce CEACAM1a-independent cell-to-cell fusion as well as neuroattenuation (Matsuyama and Taguchi 2002a, b; Taguchi and Matsuyama 2002)." . _:b7430106 . _:b7430074 . _:b7430107 . _:b7430174 "Interestingly, while CD8 T cell-mediated cytolysis appears to be important for clearance of MHV from astrocytes and microglia (Stohlman et al. >>1995<<), viral clearance from oligodendrocytes instead relies on IFN-\u03B3 secretion, as indicated by the persistence of the JHM variant 2.2-V-1 in oligodendrocytes of IFN-\u03B3-deficient mice (Parra et al. 1999)." . _:b7430187 . _:b7429936 "the spike glycoprotein with its cellular receptor CEACAM1a (Williams et al. 1991) and fuses either at the cell surface or from within endosomes, likely depending on target cell type and MHV strain (Gallagher et al. 1991; Kooi et al. >>1991<<; Nash and Buchmeier 1997). Following entry, viral replication occurs in the cytoplasm." . _:b7430116 . _:b7430045 . _:b7430117 . _:b429914715 . _:b7429935 "via interaction of the spike glycoprotein with its cellular receptor CEACAM1a (Williams et al. 1991) and fuses either at the cell surface or from within endosomes, likely depending on target cell type and MHV strain (Gallagher et al. >>1991<<; Kooi et al. 1991; Nash and Buchmeier 1997). Following entry, viral replication occurs in the cytoplasm." . _:b7430118 . . _:b7430119 . _:b7430112 . _:b7430113 . _:b7430114 . _:b7430115 . . _:b429914901 . _:b7430124 . _:b7430172 . . _:b7430125 . _:b7430126 . _:b429914661 . _:b7430127 . _:b7430056 "A L1114F substitution has also been identified in the spike of the 2.2-V-1 glial-tropic variant of JHM-DL (Wang et al. >>1992<<) and in the spike of the highly attenuated soluble receptor-resistant mutant srr7 derived from JHM cl-2 (Saeki et al. 1997, 1998)." . _:b7430120 . _:b429914917 . _:b7430176 . . _:b429914608 . . . _:b7430121 . _:b7430122 . _:b7430123 . _:b7430132 . _:b429914749 . _:b429914570 . _:b429914701 . _:b7430133 . _:b7429924 . . _:b7430134 . . _:b7430135 . . _:b7430128 . _:b429914518 . _:b7430129 . _:b7430130 . _:b7429922 . . _:b7430131 . . _:b429914492 . _:b7430140 . _:b7430061 "1; Yokomori et al. >>1989<<; Kienzle et al. 1990; Yokomori et al. 1991; Smits et al. 2005)." . _:b7430141 . _:b7430142 . . _:b7430143 . . _:b7430173 "not required for, clearance of MHV from the CNS; furthermore, JHM-infected perforin-deficient mice still developed encephalomyelitis and demyelination, indicating that these processes are independent of perforin activity (Lin et al. >>1997<<). Interestingly, while CD8 T cell-mediated cytolysis appears to be important for clearance of MHV from astrocytes and microglia (Stohlman et al. 1995), viral clearance from oligodendrocytes instead relies on IFN-\u03B3 secretion, as indicated" . _:b7430136 . _:b7430160 "or sublethally irradiated wild-type mice have demonstrated that the host adaptive immune response plays a pivotal role in viral clearance (Wang et al. 1990; Houtman and Fleming 1996; Wu and Perlman 1999; Matthews et al. >>2002<<). Subsequent studies in mice lacking individual lymphocyte populations, either due to antibody depletion or genetic manipulation, combined with reconstitution experiments in mice lacking these lymphocytes have more clearly delineated the" . _:b7430137 . _:b7430138 . . _:b7430013 . _:b7430139 . _:b7430184 "were detected beginning as early as day\u00A010 post-infection in wild-type mice with hindlimb paralysis but not in persistently infected SCID mice, suggesting that epitope escape occurs only in the presence of immune pressure (Pewe et al. >>1997<<). Subsequent studies showed that increased levels of MHV-specific antibody in the CNS reduced the emergence of MHC class I-restricted epitope escape mutants by preventing the onset of chronic disease in the suckling mouse model (Dandekar" . . _:b429914667 . . _:b429914616 . _:b7430075 "The M protein of a porcine coronavirus, transmissible gastroenteritis virus (TGEV), induces type I interferon, and mutations that reduce glycosylation of M decrease this activity (Laude et al. >>1992<<). While the M protein of MHV is O-glycosylated, glycosylation is not essential for either viral assembly or infectivity; furthermore, the glycosylation state of M (N-, O-, or no glycosylation) does not affect MHV replication in vitro." . _:b7429985 "subacute demyelinationGlial cells, primarily oligodendrocytesL1114F; CEACAM1-dependent spreadFleming et al. (1986), Wang et al. (1992)JHM cl-2Highly lethalNeurons, glial cellsGly310; Leu1114; CEACAM1-independent spreadTaguchi et al. (>>1985<<)srr7 (soluble receptor-resistant mutant of JHM cl-2)NeuroattenuatedMacrophages/microglia (in vitro)L1114F; CEACAM1-dependent spreadMatsuyama et al. (2001), Nakagaki and Taguchi (2005)JHM." . _:b7430168 "SD isolate induces a weak antiviral CD8 T cell response in the brain compared to other neurotropic strains (Rempel et al. 2004b; Iacono et al. >>2006<<); infectious virus is not cleared and mice typically succumb to infection by day\u00A07 post-infection." . . . _:b7430126 "Importantly, the abrogation of IFNAR expression had little effect on the function of virus-specific CD8 T cells, illustrating the importance of the type I IFN response even in the presence of a robust T cell response (Ireland et al. >>2008<<)." . . . _:b429914669 . . _:b429914482 . _:b429914697 . _:b429914848 . . _:b429914563 . . _:b429914890 . . . . . _:b429914894 . _:b7430130 . _:b429914630 . _:b7430073 "There were early studies both supporting and arguing against a role for HE in MHV pathogenesis (Taguchi et al. 1986; LaMonica et al. 1991; Yokomori et al. 1992, 1993, >>1995<<). However, these studies were not able to distinguish between the effects of HE and the influence of other genes in the comparison of various MHV isolates. It is clear that expression of the viral HE glycoprotein is not essential for" . _:b429914528 . _:b429914613 . _:b429914631 . . . _:b7430167 . _:b7430130 "Cervantes-Barragan et al. (>>2009<<) showed that type I IFN signaling was most important in bone marrow-derived cells, specifically macrophages and dendritic cells, and to a much lesser extent in parenchymal cells to control viral replication and spread in a model of" . _:b7430114 . . _:b7430058 "has also been identified in the spike of the 2.2-V-1 glial-tropic variant of JHM-DL (Wang et al. 1992) and in the spike of the highly attenuated soluble receptor-resistant mutant srr7 derived from JHM cl-2 (Saeki et al. 1997, >>1998<<). These substitutions are associated with an inability to induce CEACAM1a-independent cell-to-cell fusion as well as neuroattenuation (Matsuyama and Taguchi 2002a, b; Taguchi and Matsuyama 2002)." . _:b7430016 . _:b429914742 . . . . _:b7430111 . _:b7429992 . . _:b7430190 "of monoclonal antibodies specific for individual viral proteins has been shown to protect against lethal MHV infection, though evidence of sublethal infection and demyelination was still detected (Buchmeier et al. 1984; Wege et al. >>1984<<; Nakanaga et al. 1986)." . _:b7429919 "introduction" . _:b7429928 . _:b7430034 "4; Frana et al. >>1985<<; Luytjes et al. 1988). Spike is expressed on the virion membrane as a trimer in which the S1 subunits form a globular head structure and the S2 subunits form a transmembrane stalk (Fig." . . _:b7430151 . _:b7429921 "Several human coronaviruses have been identified, including the mild respiratory pathogens HCoV-229E (Hamre and Procknow >>1966<<) and HCoV-OC43 (McIntosh et al. 1967), an etiologic agent of croup known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al." . _:b7430139 . _:b7430041 "SD (Dalziel et al. 1986; Ontiveros et al. >>2003<<), JHM cl-2 (Taguchi et al. 1985), and JHM-DL (Wang et al. 1992)." . _:b7430146 . . _:b7430146 . _:b7429964 "The persistence of viral RNA, both genome and mRNA (unpublished data), and likely low levels of viral antigen within the CNS are responsible for the maintenance of T cells in the CNS during chronic disease (Ramakrishna et al. >>2004<<, 2006). Furthermore, expression of CXCL10 (IP-10) and CCL5 (RANTES), which attract T cells and macrophages respectively, remains elevated during late disease, and the observation that antibody depletion of either CXCL10 or CCL5 results in" . _:b429914831 . . . _:b7430037 . _:b429914640 . _:b7430023 "viral proteins and pathogenesis" . _:b429914741 . _:b7429970 . _:b7430022 "the more distantly related pregnancy-specific glycoprotein family, was identified in the brain due to its weak homology with ceacam1a; curiously, psg16 was reported to function in vitro as a receptor for A59 but not JHM (Chen et al. >>1995<<). Still, it remains possible that an alternative receptor used by MHV in the brain may be completely unrelated to CEACAM1a, making its identification more difficult." . _:b429914870 . _:b7430095 . _:b7429986 "glial cellsGly310; Leu1114; CEACAM1-independent spreadTaguchi et al. (1985)srr7 (soluble receptor-resistant mutant of JHM cl-2)NeuroattenuatedMacrophages/microglia (in vitro)L1114F; CEACAM1-dependent spreadMatsuyama et al. (>>2001<<), Nakagaki and Taguchi (2005)JHM.IAHighly lethal, but less than JHM.SDNeurons, glial cellsSer310; Leu1114; CEACAM1-dependent spreadOntiveros et al. (2003)rJIA." . _:b429914866 . _:b429914738 . _:b7430021 "The alternative ceacam1b allele expressed by MHV-resistant mice can similarly mediate infection with A59 when overexpressed in vitro (Dveksler et al. 1993b). While the relative efficiencies of these alternative receptors are unclear, the decreased infection efficiency observed is likely attributable to sequence differences within the MHV binding site in the N-terminal domain. Yet another" . _:b7430154 . . _:b7430097 . _:b7429987 "Leu1114; CEACAM1-independent spreadTaguchi et al. (1985)srr7 (soluble receptor-resistant mutant of JHM cl-2)NeuroattenuatedMacrophages/microglia (in vitro)L1114F; CEACAM1-dependent spreadMatsuyama et al. (2001), Nakagaki and Taguchi (>>2005<<)JHM.IAHighly lethal, but less than JHM.SDNeurons, glial cellsSer310; Leu1114; CEACAM1-dependent spreadOntiveros et al. (2003)rJIA." . _:b429914912 . _:b7430044 . . . . _:b7430066 . . _:b429914800 . _:b7430193 . _:b429914721 . _:b7430046 "neurovirulence of these viruses is due, at least in part, to their ability to induce cell-to-cell fusion and viral spread in the absence of the receptor CEACAM1a (Gallagher et al. 1992, Dalziel et al. 1986; Gallagher and Buchmeier >>2001<<). This lack of requirement for CEACAM1a is associated with a less stable association of S1 and S2 such that the conformational changes that lead to fusion are more easily triggered, even in the absence of CEACAM1a (Gallagher and Buchmeier" . _:b429914546 . . . _:b7429960 "Furthermore, transfer of either CD4 or CD8 T cells also restores the development of demyelination in RAG-deficient mice, perhaps by triggering astrocytes to produce chemokines (Lane et al. >>1998<<). Thus, while either CD4 or CD8 T cells are sufficient to promote demyelination, neither cell type is essential (Wu et al. 2000; Matthews et al. 2002). Infection of B cell-deficient mice similarly confirmed that this cell type is also not" . _:b7430073 . _:b7430089 "Finally, the N protein of A59 was shown to antagonize type I interferon by blocking RNase L activity in vitro when expressed from a recombinant vaccinia virus (Ye et al. >>2007<<)." . . _:b429914789 . . . _:b429914728 . . . _:b7430100 . . . . . _:b429914745 . _:b429914642 . _:b7429989 "IANeurons, glial cellsS310G; CEACAM1-independent spreadOntiveros et al. (>>2003<<)A59Neuroattenuated; mild encephalitis; subacute demyelination; hepatitisNeurons, glial cellsHVR deletion (52 aa); CEACAM1-dependent spreadLavi et al. (1984a, b) Fig." . . _:b429914763 . _:b429914581 . _:b7429932 . . . . _:b7430106 . . . . _:b7430038 "Interestingly, a single amino acid substitution, Q159L, within the RBD eliminates the ability of A59 to infect the liver while having no measurable effect on neurovirulence (Leparc-Goffart et al. >>1997<<; Leparc-Goffart et al. 1998)." . _:b7429973 . . _:b429914566 . _:b7430065 "Thus, it had long been speculated that HE may play a role in acute and/or chronic MHV disease, either as a determinant of organ and/or cellular tropism (Yokomori et al. 1992, >>1993<<, 1995) or to aid in spread of the virus (Kienzle et al. 1990)." . _:b7430095 "replicated with similar kinetics and to a similar titer as wild-type A59 virus in murine 17Cl-1 fibroblasts, it was attenuated in its ability to replicate in the liver and cause hepatitis (Zust et al. 2007; Narayanan et al. >>2008<<). There are data suggesting that the nsp1 proteins of both MHV and SARS-CoV have the ability to inhibit the synthesis and/or signaling activities of IFN-\u03B2 (Wathelet et al. 2007)." . _:b7430168 . _:b7430044 "The extremely high neurovirulence of these viruses is due, at least in part, to their ability to induce cell-to-cell fusion and viral spread in the absence of the receptor CEACAM1a (Gallagher et al. >>1992<<, Dalziel et al. 1986; Gallagher and Buchmeier 2001)." . _:b7429940 "Demyelinated lesions, such as those resulting from A59 infection, are usually assessed by staining of spinal cord sections with Luxol Fast Blue and are maximal at 1\u00A0month post-infection (Lavi et al. 1984b; Das Sarma et al. 2000; Matthews et al. 2002; MacNamara et al. 2005a)." . . . _:b7430171 . _:b7429996 "2; Ontiveros et al. >>2003<<). The degree of viral spread throughout the brain and spinal cord, tropism of virus for individual CNS cell types, and dissemination of virus to other organs is largely dependent on viral strain (Table\u00A01)." . _:b429914535 . _:b7430008 "Despite the high predilection of some MHV strains for cells of the CNS, expression of CEACAM1a is relatively low in neural tissue compared to other MHV targets, such as liver and intestine (Godfraind et al. >>1995<<). CEACAM1a is highly expressed on epithelia, endothelia, and cells of hematopoietic origin, including macrophages, B cells, and activated T cells (Coutelier et al. 1994; Godfraind et al. 1995; Nakajima et al. 2002). In the brain, only" . . . . . _:b7429957 "both monocyte-derived macrophages and microglia are present in regions of demyelination and can be seen in contact with demyelinated axons, suggesting that both cell types participate in the demyelinating process (Templeton et al. >>2008<<). The JHM-infected RAG-deficient mouse model, developed by Stanley Perlman and colleagues, has also been useful in dissecting the factors necessary for immune-mediated demyelination." . _:b429914842 . _:b7430159 "gene (RAG)-deficient, or sublethally irradiated wild-type mice have demonstrated that the host adaptive immune response plays a pivotal role in viral clearance (Wang et al. 1990; Houtman and Fleming 1996; Wu and Perlman >>1999<<; Matthews et al. 2002)." . . _:b7430145 . . _:b7429929 "Despite its name, not all strains of MHV are hepatotropic, with individual isolates inducing respiratory, enteric, or neurologic disease alone or in combination with hepatitis (Weiss and Navas-Martin >>2005<<). While enteric strains are typically responsible for MHV outbreaks in housed rodent colonies (Homberger et al. 1998), the most frequently studied are the neurotropic strains due to their ability to induce acute encephalomyelitis with or" . _:b429914557 . _:b7430147 . . _:b7430150 "The spike gene has been demonstrated to be a determinant of neurovirulence and to influence macrophage, but not T cell, infiltration into the brain (Phillips et al. 1999, >>2002<<; Rempel et al. 2004a; Iacono et al. 2006)." . . _:b7429976 "Leslie Weiner later serially passaged this virus multiple times through mouse brains (Weiner 1973; Weiner et al. >>1973<<). Most JHM isolates used since, including those described below, were derived from this mouse-passaged virus. The A59 strain was isolated independently in 1961 from a mouse with leukemia (Manaker et al. 1961). Table" . _:b7430152 . _:b7430064 "Thus, it had long been speculated that HE may play a role in acute and/or chronic MHV disease, either as a determinant of organ and/or cellular tropism (Yokomori et al. >>1992<<, 1993, 1995) or to aid in spread of the virus (Kienzle et al. 1990)." . _:b7430153 . _:b7430094 "an nsp1 A59 mutant (MHV-nsp1\u039499) replicated with similar kinetics and to a similar titer as wild-type A59 virus in murine 17Cl-1 fibroblasts, it was attenuated in its ability to replicate in the liver and cause hepatitis (Zust et al. >>2007<<; Narayanan et al. 2008). There are data suggesting that the nsp1 proteins of both MHV and SARS-CoV have the ability to inhibit the synthesis and/or signaling activities of IFN-\u03B2 (Wathelet et al. 2007)." . _:b7429949 "neuroattenuated variants of JHM, such as 2.2-V-1 (Fleming et al. 1986; Marten et al. 2000b), the less neurovirulent A59 strain (Lavi et al. 1984b; MacNamara et al. 2005a), or infection of passively immunized suckling mice (Pewe et al. >>1996<<). The use of these models ensures enough survivors of acute infection to allow the study of demyelination." . _:b429914719 . _:b7430175 "and microglia (Stohlman et al. 1995), viral clearance from oligodendrocytes instead relies on IFN-\u03B3 secretion, as indicated by the persistence of the JHM variant 2.2-V-1 in oligodendrocytes of IFN-\u03B3-deficient mice (Parra et al. >>1999<<). Though several neurotropic MHV strains infect large numbers of neurons in addition to glial cells, mechanisms of MHV control in this unique cell type are poorly understood." . _:b429914823 . . . . . _:b7430039 . _:b429914597 . _:b7430101 "The PLP of SARS-CoV and the analogous PLP-2 of MHV were also shown to have deubiquitinating activity, and it was suggested that this activity could confer a role as a type I IFN antagonist (Barretto et al. 2005; Zheng et al. >>2008<<). Indeed, several studies have demonstrated that the PLP of SARS-CoV inhibits both the IRF3 and NF-\u03BAB pathways (Devaraj et al. 2007; Frieman et al. 2009). However, there are conflicting data regarding the role of MHV PLP-2 as a type I IFN" . . _:b7430069 . . . _:b7430112 "While CPD activity has not yet been demonstrated for the MHV ns2 protein, the ADRPs of several coronaviruses (including SARS-CoV, HCoV-229E, and porcine TGEV) were demonstrated to have phosphatase activity (Putics et al. >>2005<<, 2006a). In addition, the ADRP also has binding activity to mono- and poly-ADP-ribose, implying that it may participate in ribosylation of host cell proteins, which may promote apoptosis or necrosis (Egloff et al. 2006)." . _:b429914845 . _:b7429954 "MHV-induced demyelination is characterized by inflammatory infiltrates consisting of lymphocytes and lipid-containing macrophages (Stohlman and Weiner >>1981<<; Lavi et al. 1986a, b; Wu and Perlman 1999)." . . _:b7430078 . . _:b429914903 . _:b7429967 . . . _:b7430110 "2003) in which the CPD would convert ADP-ribose-1\u2033,2\u2033-cyclic phosphate into ADP-ribose 1\u2033 phosphate and the ADRP would convert the product of the CPD, ADP-ribose 1\u2033 phosphate, into ADP-ribose and inorganic phosphate (Putics et al. >>2005<<, 2006b). While CPD activity has not yet been demonstrated for the MHV ns2 protein, the ADRPs of several coronaviruses (including SARS-CoV, HCoV-229E, and porcine TGEV) were demonstrated to have phosphatase activity (Putics et al. 2005," . . _:b7430161 "While both CD4 and CD8 T cells have been shown to be required for effective control of MHV infection in the CNS (Williamson and Stohlman >>1990<<), CD8 T cells are most directly responsible for clearance of infectious virus." . . _:b429914907 . _:b429914635 . _:b7430147 "as well as prolonged expression of IFN-\u03B2, whereas A59 infection is characterized predominantly by T cell infiltration into the brain consistent with higher levels of T cell-attracting chemokines (Rempel et al. 2004a, b; Iacono et al. >>2006<<; Scott et al. 2008)." . . . . . _:b429914760 . _:b7429985 . . _:b429914748 . . _:b429914655 . _:b7430180 . . _:b7430170 . _:b7430187 "suckling mice displayed increased morbidity and mortality compared to parental JHM upon infection of naive suckling mice, suggesting that the escape from the response to S510 is a determinant of virulence and disease (Pewe et al. >>1998<<). Interestingly, in contrast to suckling mice, similar epitope escape mutants were slightly attenuated when used to infect weanling mice." . _:b7429953 "The extent of viral spread during acute infection is an important predictor of the development of late demyelination (Marten et al. 2000b; MacNamara et al. 2005b) and is determined by the inherent ability of the virus strain to spread among CNS cell types balanced by the ability of the host to clear virus, which is largely determined by the CD8 T cell response." . _:b7430009 "CEACAM1a is highly expressed on epithelia, endothelia, and cells of hematopoietic origin, including macrophages, B cells, and activated T cells (Coutelier et al. >>1994<<; Godfraind et al. 1995; Nakajima et al. 2002)." . . _:b429914602 . _:b7430011 . _:b7430149 . _:b7430189 "Passive transfer of monoclonal antibodies specific for individual viral proteins has been shown to protect against lethal MHV infection, though evidence of sublethal infection and demyelination was still detected (Buchmeier et al. >>1984<<; Wege et al. 1984; Nakanaga et al. 1986)." . _:b7429978 . _:b429914510 . _:b7430142 "rapid spread of viral antigen through the brain accompanied by greater levels of infiltrating neutrophils and macrophages, as well as increased cellular destruction, compared to the weakly neurovirulent A59 strain (Rempel et al. 2004a, b; Iacono et al. 2006). While infiltrating neutrophils had a protective effect for animals infected with the attenuated, glial-tropic JHM variant 2.2-V-1 (Zhou et al. 2003), neutrophil depletion studies using the highly neurovirulent JHM." . _:b429914567 . _:b429914758 . . _:b429914672 . _:b7430051 "SD, such as V5A13.1 (Fazakerley et al. 1992), are associated with single site mutations and/or deletions within the HVR (Dalziel et al. 1986; Gallagher et al. 1990; Phillips et al. >>2001<<). Consistent with the comparison of different JHM spikes, the genome of the neuroattenuated A59 strain encodes a large deletion (52 aa) within the HVR. However, replacement of the HVR of A59 with that of JHM.SD did not confer a highly" . . . _:b7430158 "(SCID), recombination-activating gene (RAG)-deficient, or sublethally irradiated wild-type mice have demonstrated that the host adaptive immune response plays a pivotal role in viral clearance (Wang et al. 1990; Houtman and Fleming >>1996<<; Wu and Perlman 1999; Matthews et al. 2002)." . _:b429914839 . _:b7430066 "Thus, it had long been speculated that HE may play a role in acute and/or chronic MHV disease, either as a determinant of organ and/or cellular tropism (Yokomori et al. 1992, 1993, >>1995<<) or to aid in spread of the virus (Kienzle et al. 1990)." . . . _:b429914850 . _:b429914833 . . . _:b429914571 . _:b429914856 . _:b429914854 . . _:b7430167 "SD isolate induces a weak antiviral CD8 T cell response in the brain compared to other neurotropic strains (Rempel et al. 2004b; Iacono et al. 2006); infectious virus is not cleared and mice typically succumb to infection by day\u00A07 post-infection." . _:b7429978 "SD (MHV-4)Highly lethal; severe encephalitisNeurons, glial cellsGly310; Leu1114; CEACAM1-independent spreadDalziel et al. (>>1986<<)V5A13.1 (mAb escape mutant of JHM." . . . _:b429914479 . _:b7429942 "lesions, such as those resulting from A59 infection, are usually assessed by staining of spinal cord sections with Luxol Fast Blue and are maximal at 1\u00A0month post-infection (Lavi et al. 1984b; Das Sarma et al. 2000; Matthews et al. >>2002<<; MacNamara et al. 2005a)." . . _:b7430166 "in the draining cervical lymph nodes (CLN) by day\u00A03 post-infection, followed by further expansion in the spleen and ultimate accumulation in the brain at the initial site of infection, peaking at day\u00A07 post-infection (Marten et al. >>2003<<). These results suggest that the CLN are the initial site of CD8 T cell priming during neurotropic MHV infection." . . . . _:b7430039 "Interestingly, a single amino acid substitution, Q159L, within the RBD eliminates the ability of A59 to infect the liver while having no measurable effect on neurovirulence (Leparc-Goffart et al. 1997; Leparc-Goffart et al. >>1998<<)." . . . . . _:b429914882 . . _:b7429923 "Several human coronaviruses have been identified, including the mild respiratory pathogens HCoV-229E (Hamre and Procknow 1966) and HCoV-OC43 (McIntosh et al. 1967), an etiologic agent of croup known as HCoV-NL63 (Chiu et al. >>2005<<; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. 2003; Ksiazek et al. 2003; Peiris et al. 2003; Osterhaus et al. 2004)." . _:b429914549 . . _:b429914750 . _:b429914802 . _:b429914484 . . _:b7430163 "The importance of CD8 T cells in the control of MHV is further supported by the increased susceptibility and delayed viral clearance observed in \u03B22-microglobulin-deficient mice compared to wild-type control mice (Lavi et al. >>1999<<). Using a model in which C57BL/6 mice were infected with a recombinant A59 virus expressing the GP33 epitope of lymphocytic choriomeningitis virus (LCMV), it was shown that adoptive transfer of naive, GP33-specific CD8 T cells resulted in" . _:b429914565 . _:b7429953 . _:b7430090 . _:b7430005 "Using recombinant CEACAM1a constructs with deletions within the extracellular domains, the site of MHV binding was shown to be within the N-terminal domain (D1; Dveksler et al. 1993a). This N-terminal domain is present in all four murine CEACAM1a isoforms; thus, all serve as functional MHV receptors. Interestingly, long-tailed CEACAM1a isoforms contain phosphorylatable tyrosine residues within immunoreceptor" . . _:b429914685 . . _:b7429987 . . _:b7430019 "SD to cause disease in these mice was mapped to the spike gene (Hemmila et al. 2004; Miura et al. >>2008<<). While this finding is intriguing, it is unclear whether the inability of A59 to cause disease in ceacam1a\u2212/\u2212 mice is due to a lack of initial infection or deficiency in cell-to-cell spread in the CNS in the absence of CEACAM1a. In vitro" . _:b429914515 . "10.1007%2Fs11481-010-9202-2" . . _:b7430042 "SD (Dalziel et al. 1986; Ontiveros et al. 2003), JHM cl-2 (Taguchi et al. >>1985<<), and JHM-DL (Wang et al. 1992)." . . . _:b429914543 . . _:b7430015 . _:b7429921 . _:b429914805 . . _:b7430100 "The PLP of SARS-CoV and the analogous PLP-2 of MHV were also shown to have deubiquitinating activity, and it was suggested that this activity could confer a role as a type I IFN antagonist (Barretto et al. >>2005<<; Zheng et al. 2008)." . _:b429914494 . . _:b429914499 . . _:b429914829 . . _:b7429993 "Viral titers typically peak at day\u00A05 post-infection and then begin to decline (Leparc-Goffart et al. 1998), with infectious virus becoming undetectable by approximately 2\u00A0weeks post-infection (Matthews et al. >>2001<<). Innate immune responses are apparent within the first few days of infection and then give way to adaptive immunity. CD8 T cells, which play a dominant role in controlling virus replication, are most numerous in the brain at day\u00A07" . . . _:b7430062 . . . _:b429914702 . _:b429914747 . _:b429914720 . . _:b429914881 . . _:b7429961 . _:b429914815 . _:b429914480 . _:b7430080 . _:b7430043 . _:b7430065 . _:b7429940 . _:b7430140 "on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. 2001; Glass et al. 2002; Rempel et al. 2004b; Bergmann et al. 2006; Iacono et al. 2006; Savarin et al. 2008; Scott et al. >>2008<<)." . . . . _:b7430030 . . _:b7429986 . _:b7429941 "Demyelinated lesions, such as those resulting from A59 infection, are usually assessed by staining of spinal cord sections with Luxol Fast Blue and are maximal at 1\u00A0month post-infection (Lavi et al. 1984b; Das Sarma et al. >>2000<<; Matthews et al. 2002; MacNamara et al. 2005a)." . _:b429914908 . . _:b7430091 "However, this effect occurs via induction of fibrinogen-like protein 2 (fgl2; Parr et al. >>1995<<; Ning et al. 1999, 2005) by the N proteins of hepatotropic MHV-3 and A59 strains, and there is no evidence to suggest that fgl2 plays a role in CNS pathogenesis." . _:b7430072 . _:b429914837 . _:b429914785 . _:b7429947 . . _:b7430013 "In the brain, only endothelial cells and microglia have been shown to express CEACAM1a protein (Godfraind et al. 1997; Ramakrishna et al. >>2004<<). Yet, perhaps paradoxically, many neurotropic MHV strains are able to infect a wide range of CNS cell types in addition to endothelial cells and microglia, including neurons, astrocytes, and oligodendrocytes. It has been suggested for" . . _:b7430067 . _:b429914612 . _:b429914752 . _:b7430056 . _:b429914911 . . _:b7430017 . _:b7430138 . _:b7430121 "immune responses to mhv" . _:b7430018 . _:b429914853 . . . _:b7430030 "recombinant MHV strains differing only in spike has definitively demonstrated the important role of spike in determining neurovirulence during infection in the mouse (Phillips et al. 1999, 2002; Navas and Weiss 2003; Iacono et al. >>2006<<). The replacement of the A59 spike gene with the spike of JHM.SD (rA59/SJHM) confers high neurovirulence on the resulting virus (Phillips et al. 1999; Navas and Weiss 2003)." . . _:b7430143 . _:b429914744 . . _:b7430158 . . _:b7430088 . _:b7430051 . _:b7430175 . _:b429914819 . . _:b429914716 . . . . _:b7430060 . _:b7430003 . _:b7430052 . _:b7430076 "However, the glycosylation type may affect the ability of MHV M to induce IFN-\u03B1 in vitro and also to replicate in the mouse liver (de Haan et al. >>2003<<)." . . _:b429914737 . _:b429914651 . _:b7430014 . . . _:b7430135 . . _:b429914475 . _:b7430141 "by rapid spread of viral antigen through the brain accompanied by greater levels of infiltrating neutrophils and macrophages, as well as increased cellular destruction, compared to the weakly neurovirulent A59 strain (Rempel et al. 2004a, b; Iacono et al. 2006). While infiltrating neutrophils had a protective effect for animals infected with the attenuated, glial-tropic JHM variant 2.2-V-1 (Zhou et al. 2003), neutrophil depletion studies using the highly neurovirulent JHM." . . _:b7430050 "SD, such as V5A13.1 (Fazakerley et al. 1992), are associated with single site mutations and/or deletions within the HVR (Dalziel et al. 1986; Gallagher et al. >>1990<<; Phillips et al. 2001)." . _:b429914784 . _:b7430138 "and the chemokines secreted are dependent on MHV strain and contribute to the severity of disease, as described and reviewed elsewhere (Marten et al. 2001; Glass et al. 2002; Rempel et al. 2004b; Bergmann et al. 2006; Iacono et al. >>2006<<; Savarin et al. 2008; Scott et al. 2008)." . . . _:b7430107 "The ns2 protein contains a domain with high homology to a superfamily of proteins known as 2H phosphoesterases and is thus predicted to have a 1\u2033,2\u2033-cyclophosphodiesterase (CPD) activity (Snijder et al. >>2003<<). Together, the putative CPD domain and the ADRP domain could potentially participate in a pathway of nucleotide processing (Gorbalenya et al. 1991; Snijder et al. 2003) in which the CPD would convert ADP-ribose-1\u2033,2\u2033-cyclic phosphate" . _:b429914478 . _:b7430077 . _:b429914621 . _:b7429991 . _:b429914478 "9"^^ . _:b429914479 "7"^^ . . _:b429914477 "11"^^ . _:b429914708 . . _:b429914476 "12"^^ . _:b429914475 "12"^^ . . . . _:b429914486 "6"^^ . _:b429914487 "6"^^ . . _:b429914484 "6"^^ . . . . _:b429914485 "6"^^ . _:b429914599 . _:b7429995 . _:b429914482 "6"^^ . _:b429914483 "6"^^ . _:b429914480 "7"^^ . . _:b429914481 "7"^^ . _:b429914919 . . . . _:b429914493 "5"^^ . _:b429914492 "5"^^ . . . _:b429914700 . _:b429914495 "5"^^ . _:b429914624 . _:b429914494 "5"^^ . _:b429914490 "6"^^ . _:b429914491 "6"^^ . _:b7430178 . _:b429914488 "6"^^ . _:b429914483 . . _:b429914489 "6"^^ . _:b7429974 "John Howard Mueller, was initially isolated by Cheever, Bailey, and colleagues in 1949 from the brain of a paralyzed mouse and shown to induce encephalitis with extensive destruction of myelin (Bailey et al. 1949; Cheever et al. >>1949<<). Dr. Leslie Weiner later serially passaged this virus multiple times through mouse brains (Weiner 1973; Weiner et al. 1973)." . . _:b429914501 "5"^^ . . _:b7430131 "This result is in contrast to the studies described above in which IFNAR signaling was essential for control of spread of virus following intracranial inoculation (Ireland et al. >>2008<<; Roth-Cross et al. 2008)." . _:b429914500 "5"^^ . _:b7429951 "This result is in contrast to the Theiler\u2019s virus-induced demyelination mouse model, in which there is persistence of infectious virus (Stohlman and Hinton >>2001<<)." . _:b429914879 . _:b429914503 "5"^^ . _:b429914502 "5"^^ . . _:b7430059 . _:b429914497 "5"^^ . _:b429914699 . _:b429914496 "5"^^ . . _:b429914499 "5"^^ . _:b429914498 "5"^^ . _:b429914509 "5"^^ . _:b429914508 "5"^^ . _:b429914511 "4"^^ . _:b429914510 "4"^^ . . _:b429914505 "5"^^ . _:b7430171 "SD, perhaps due, at least in part, to the effects of antiviral CD8 T cells (Phillips et al. 1999; Iacono et al. >>2006<<). These studies further suggest that even a robust CD8 T cell response may be insufficient to control infection with highly neurovirulent MHV strains." . _:b7430144 "While infiltrating neutrophils had a protective effect for animals infected with the attenuated, glial-tropic JHM variant 2.2-V-1 (Zhou et al. >>2003<<), neutrophil depletion studies using the highly neurovirulent JHM." . . . _:b429914504 "5"^^ . _:b429914537 . . _:b429914507 "5"^^ . _:b7430164 . . _:b429914506 "5"^^ . _:b7429990 . _:b7429947 . _:b429914517 "4"^^ . . . _:b7429939 . _:b429914516 "4"^^ . . _:b429914519 "4"^^ . _:b7430149 "The spike gene has been demonstrated to be a determinant of neurovirulence and to influence macrophage, but not T cell, infiltration into the brain (Phillips et al. >>1999<<, 2002; Rempel et al. 2004a; Iacono et al. 2006)." . _:b429914518 "4"^^ . _:b429914513 "4"^^ . . . . _:b429914512 "4"^^ . . _:b429914515 "4"^^ . _:b429914552 . _:b429914514 "4"^^ . . . . _:b429914525 "4"^^ . _:b429914827 . _:b429914524 "4"^^ . _:b7429919 . _:b429914527 "4"^^ . . . _:b7429995 . _:b429914526 "4"^^ . _:b7429980 "SD isolated from persistently infected OBL21A cells)NeuroattenuatedOlfactory bulb neuronsL1114R; CEACAM1-dependent spreadGallagher et al. (1991), Pearce et al. (>>1994<<)JHM-DLHighly lethalNeurons, glial cellsLeu1114Stohlman et al. (1982), Wang et al. (1992)2.2-V-1 (mAb escape mutant of JHM-DL)Neuroattenuated; subacute demyelinationGlial cells, primarily oligodendrocytesL1114F; CEACAM1-dependent" . _:b429914521 "4"^^ . _:b429914794 . _:b429914520 "4"^^ . _:b429914586 . _:b429914523 "4"^^ . _:b429914790 . . _:b429914522 "4"^^ . _:b7430087 "N has also been implicated to play a role in translation of viral mRNA (Tahara et al. >>1998<<). Furthermore, MHV N has been reported to associate with microtubules in a neuronal cell line in vitro (Pasick et al. 1994), suggesting a possible role for N in trafficking and axonal transport. Finally, the N protein of A59 was shown to" . _:b429914533 "4"^^ . _:b429914817 . . _:b7429988 "SDNeurons, glial cellsSer310; Leu1114; CEACAM1-dependent spreadOntiveros et al. (>>2003<<)rJIA.S310G (mutant of JHM.IA)Highly lethal; more than JHM.IANeurons, glial cellsS310G; CEACAM1-independent spreadOntiveros et al. (2003)A59Neuroattenuated; mild encephalitis; subacute demyelination; hepatitisNeurons, glial cellsHVR" . _:b429914532 "4"^^ . _:b429914535 "3"^^ . . _:b429914534 "3"^^ . _:b429914846 . _:b429914529 "4"^^ . _:b7430110 . . . _:b429914528 "4"^^ . _:b7429997 . . _:b429914531 "4"^^ . . _:b429914530 "4"^^ . . . _:b429914541 "3"^^ . _:b7430042 . . _:b7429971 . _:b429914540 "3"^^ . . . _:b429914543 "3"^^ . _:b429914688 . _:b429914921 . _:b429914864 . _:b429914542 "3"^^ . _:b429914740 . . _:b429914591 . _:b429914537 "3"^^ . . _:b429914618 . _:b429914536 "3"^^ . . _:b429914649 . _:b429914539 "3"^^ . _:b7430112 . . _:b429914538 "3"^^ . _:b7430108 . _:b429914549 "3"^^ . _:b429914548 "3"^^ . _:b7430084 "1; Hurst et al. >>2005<<). N plays an important role in enhancing efficiency of transcription (Compton et al. 1987) and significantly enhances recovery of infectious virus from cells transfected with genome length synthetic RNA (Grossoehme et al. 2009)." . _:b429914551 "3"^^ . _:b429914550 "3"^^ . _:b429914814 . _:b429914545 "3"^^ . . _:b7430193 "infectious virus during acute infection but subsequent viral reactivation at later times compared to wild-type mice; administration of MHV-specific antibody after initial viral control suppressed this viral recrudescence (Lin et al. >>1999<<). Interestingly, reactivation of virus in antibody-deficient mice was reported primarily in oligodendrocytes, while viral recrudescence in B cell-deficient mice was observed in both oligodendrocytes and astrocytes, suggesting an" . _:b429914544 "3"^^ . _:b429914547 "3"^^ . . _:b429914546 "3"^^ . _:b429914530 . _:b429914557 "3"^^ . _:b429914556 "3"^^ . _:b7429970 "additional secretion of TNF-\u03B1, IL-1\u03B2, IL-6, and type 2 nitric oxide synthesis (iNOS) by astrocytes may directly contribute to the dysregulation of oligodendrocyte function and resulting myelin loss (Sun et al. 1995; Grzybicki et al. >>1997<<)." . _:b7430007 "inhibitory motifs that have been shown to participate in protein\u2013protein interactions and downstream signaling cascades in a variety of cell types, including T cells (Chen et al. 2008) and dendritic cells (Kammerer et al. >>2001<<). Thus, it is tempting to speculate that MHV binding to long-tailed isoforms may trigger or modulate intracellular signaling pathways in ways that virus binding to short-tailed isoforms may not." . _:b7429939 "demyelination" . _:b429914559 "3"^^ . _:b429914558 "3"^^ . . _:b429914553 "3"^^ . _:b7430023 . _:b429914552 "3"^^ . _:b429914673 . . _:b7430182 "2.2-V-1 in the CNS, while expression of the PD-1 ligand B7-H1 is concurrently maintained on oligodendrocytes; the authors suggest that this PD-1/B7-H1 interaction contributes to CD8 T cell dysfunction during persistence (Phares et al. >>2009<<). Interestingly, recent studies by Zhao et al. have extended these findings, using adoptive transfer techniques and bone marrow chimeras to demonstrate that antiviral CD8 T cell populations are maintained during persistence in the CNS, at" . _:b429914555 "3"^^ . . . _:b429914554 "3"^^ . _:b429914662 . _:b429914565 "3"^^ . . . _:b429914564 "3"^^ . _:b429914567 "3"^^ . _:b7430148 . _:b429914822 . _:b429914496 . _:b429914566 "3"^^ . . . . _:b7430149 . _:b429914561 "3"^^ . _:b7430150 . . _:b429914560 "3"^^ . _:b7430151 . _:b429914563 "3"^^ . _:b7430144 . _:b7430121 . . _:b429914562 "3"^^ . _:b7430145 . _:b429914573 "3"^^ . _:b7430088 "Furthermore, MHV N has been reported to associate with microtubules in a neuronal cell line in vitro (Pasick et al. >>1994<<), suggesting a possible role for N in trafficking and axonal transport." . _:b7430068 "Consistent with this hypothesis, some of the highly neurovirulent JHM isolates express an HE protein while HE is not expressed by the tissue culture-adapted and weakly neurovirulent A59 strain (Shieh et al. >>1989<<). There were early studies both supporting and arguing against a role for HE in MHV pathogenesis (Taguchi et al. 1986; LaMonica et al. 1991; Yokomori et al. 1992, 1993, 1995). However, these studies were not able to distinguish between" . _:b7430146 . _:b429914572 "3"^^ . _:b7430147 . _:b429914575 "3"^^ . . _:b429914675 . _:b7430156 . _:b429914574 "3"^^ . _:b7430157 . _:b7430093 . _:b429914569 "3"^^ . _:b7430111 "in which the CPD would convert ADP-ribose-1\u2033,2\u2033-cyclic phosphate into ADP-ribose 1\u2033 phosphate and the ADRP would convert the product of the CPD, ADP-ribose 1\u2033 phosphate, into ADP-ribose and inorganic phosphate (Putics et al. 2005, 2006b). While CPD activity has not yet been demonstrated for the MHV ns2 protein, the ADRPs of several coronaviruses (including SARS-CoV, HCoV-229E, and porcine TGEV) were demonstrated to have phosphatase activity (Putics et al. 2005, 2006a)." . _:b7430158 . _:b7429952 "Early studies of MHV-induced demyelination suggested that demyelination was mediated directly by infection due to cytopathic effects of the virus on oligodendrocytes (Lampert et al. 1973; Weiner >>1973<<). While the mechanism of MHV-induced demyelination is still not well understood, it is clear that immune-mediated damage is the major mechanism of the demyelination process." . _:b429914568 "3"^^ . _:b7430159 . . _:b429914571 "3"^^ . _:b7430152 . _:b429914711 . _:b429914570 "3"^^ . _:b429914834 . _:b7430153 . _:b429914581 "3"^^ . _:b7430173 . _:b429914653 . _:b7430154 . _:b429914580 "3"^^ . . _:b7430155 . _:b7430026 "Ralph Baric (Yount et al. >>2002<<), has extended these genetic analyses to include the 5\u2032 two thirds of the genome containing the replicase gene." . _:b429914583 "3"^^ . _:b429914768 . _:b7430164 . _:b7429926 "et al. 1967), an etiologic agent of croup known as HCoV-NL63 (Chiu et al. 2005; van der Hoek et al. 2005), and most notably SARS-CoV, the causative agent of severe acute respiratory syndrome (SARS; Drosten et al. 2003; Ksiazek et al. >>2003<<; Peiris et al. 2003; Osterhaus et al. 2004)." . _:b429914582 "3"^^ . _:b7430165 . _:b429914577 "3"^^ . _:b429914786 . _:b7430166 . _:b429914576 "3"^^ . _:b429914861 . _:b7430167 . _:b429914579 "3"^^ . _:b7430136 . _:b429914799 . _:b7430160 . _:b7430116 "domain with a very weak phosphatase activity; furthermore, the binding of poly-ADP-ribose polymerase (PARP-1) to Sindbis nsp3 outside of the macro domain is believed to regulate transcription in neuronal cells (Park and Griffin 2009a, b). Though the role of the ADRP in coronavirus replication and/or pathogenesis is poorly understood, the activities associated with macro domains may vary among coronavirus groups, as a recent report suggests that the macro domain of group" . _:b429914578 "3"^^ . . _:b7430161 . . _:b429914589 "3"^^ . _:b7430141 . _:b7430162 . _:b7430084 . _:b429914588 "3"^^ . _:b429914600 . _:b7430163 . _:b429914578 . _:b429914591 "3"^^ . _:b7430172 . . _:b429914590 "3"^^ . . _:b7430173 . _:b429914585 "3"^^ . _:b7430162 "of a sublethal dose of neurotropic MHV, viral titers peak in the brain at day\u00A05 post-infection and then begin to decline, coincident with the accumulation of virus-specific CD8 T cells at the site of infection (Williamson et al. >>1991<<). The importance of CD8 T cells in the control of MHV is further supported by the increased susceptibility and delayed viral clearance observed in \u03B22-microglobulin-deficient mice compared to wild-type control mice (Lavi et al. 1999)." . _:b7430142 . . _:b7430174 . . . _:b7429998 . _:b429914584 "3"^^ . _:b429914876 . _:b7430175 . _:b429914587 "3"^^ . _:b7430168 . . _:b429914586 "3"^^ . _:b7430169 . _:b429914597 "3"^^ . . _:b7430170 . _:b429914698 . _:b429914596 "3"^^ . _:b7430171 . _:b429914599 "3"^^ . . _:b7430180 . . _:b429914916 . _:b429914598 "3"^^ . _:b7430181 . _:b429914593 "3"^^ . . _:b7430182 . _:b7430025 . _:b429914592 "3"^^ . _:b7430029 "of isogenic recombinant MHV strains differing only in spike has definitively demonstrated the important role of spike in determining neurovirulence during infection in the mouse (Phillips et al. 1999, 2002; Navas and Weiss >>2003<<; Iacono et al. 2006). The replacement of the A59 spike gene with the spike of JHM." . _:b7430183 . _:b429914899 . _:b429914595 "3"^^ . . . _:b7430176 . _:b7430080 "E proteins of several coronaviruses, including MHV, have been demonstrated to have ion channel activity (Wilson et al. >>2006<<). While the role of this channel activity is unknown, it has been speculated to function at the site of budding to enhance viral assembly and morphogenesis. A recent study proposes that the E protein of SARS-CoV may disrupt ion" . _:b429914594 "3"^^ . _:b7430177 . _:b429914605 "3"^^ . _:b429914885 . _:b7430178 . . _:b429914604 "3"^^ . _:b429914884 . _:b7430179 . . _:b429914607 "3"^^ . _:b429914887 . _:b7430188 . _:b429914606 "3"^^ . _:b429914511 . _:b429914886 . _:b7430189 . _:b429914601 "3"^^ . _:b429914881 . _:b7430190 . . _:b7430005 . _:b429914600 "3"^^ . _:b429914880 . _:b7430191 . _:b429914603 "3"^^ . _:b7430003 "These murine CEACAM1a isoforms contain either two or four extracellular immunoglobulin-like domains linked by a transmembrane domain to either a short (10 aa) or long (73 aa) cytoplasmic tail (McCuaig et al. >>1992<<, 1993). Using recombinant CEACAM1a constructs with deletions within the extracellular domains, the site of MHV binding was shown to be within the N-terminal domain (D1; Dveksler et al. 1993a). This N-terminal domain is present in all four" . _:b429914883 . _:b7430184 . . . _:b429914602 "3"^^ . _:b429914882 . _:b7430185 . _:b429914613 "3"^^ . _:b429914893 . _:b7430186 . _:b429914612 "3"^^ . _:b429914892 . _:b7430187 . _:b7430002 "of individual mouse strains to MHV; mouse strains expressing ceacam1a, including C57BL/6 and BALB/c, are highly susceptible to MHV infection whereas strains homozygous for ceacam1b, such as SJL, are resistant (Dveksler et al. 1993b)." . _:b429914615 "3"^^ . _:b429914895 . _:b429914913 . _:b429914614 "3"^^ . . _:b429914894 . _:b429914751 . _:b429914609 "3"^^ . _:b429914889 . _:b429914608 "3"^^ . _:b429914888 . _:b429914611 "3"^^ . _:b7430075 . _:b429914891 . _:b7430192 . . _:b429914610 "3"^^ . . _:b7430193 . _:b429914890 . _:b429914621 "2"^^ . _:b429914512 . _:b7430194 . _:b429914901 . _:b7430177 "Furthermore, CD4 T cells have been shown to be required for production of MHV-specific antibodies during infection with the JHM-DS variant (Williamson and Stohlman >>1990<<). Recent studies in which IFN-\u03B3- and perforin-deficient mice were reconstituted with memory CD4 T cells competent in just one of these functions and challenged with the JHM variant 2.2-V-1 suggest an additional, more direct role for CD4 T" . _:b429914620 "2"^^ . _:b429914900 . _:b7430195 . _:b429914623 "2"^^ . _:b429914903 . _:b429914622 "2"^^ . _:b429914517 . . _:b429914902 . _:b429914617 "3"^^ . _:b429914897 . _:b429914616 "3"^^ . _:b7429982 . _:b429914896 . _:b429914619 "2"^^ . _:b429914899 . . _:b7430028 . _:b429914641 . _:b429914618 "3"^^ . _:b429914888 . _:b7429984 . _:b429914898 . _:b429914909 . _:b429914908 . _:b429914863 . _:b429914476 . _:b7430102 "Indeed, several studies have demonstrated that the PLP of SARS-CoV inhibits both the IRF3 and NF-\u03BAB pathways (Devaraj et al. >>2007<<; Frieman et al. 2009)." . _:b429914911 . _:b7429983 "glial cellsLeu1114Stohlman et al. (1982), Wang et al. (1992)2.2-V-1 (mAb escape mutant of JHM-DL)Neuroattenuated; subacute demyelinationGlial cells, primarily oligodendrocytesL1114F; CEACAM1-dependent spreadFleming et al. (>>1986<<), Wang et al. (1992)JHM cl-2Highly lethalNeurons, glial cellsGly310; Leu1114; CEACAM1-independent spreadTaguchi et al. (1985)srr7 (soluble receptor-resistant mutant of JHM cl-2)NeuroattenuatedMacrophages/microglia (in vitro)L1114F;" . _:b429914910 . _:b429914905 . _:b7430169 "SD-infected brain has subsequently been shown to correlate with a lack of naive, virus-specific CD8 T cell priming and low levels of viral replication in the draining CLN compared to A59 (MacNamara et al. >>2008<<). Interestingly, studies of recombinant viruses in which the spike genes of A59 and JHM.SD were exchanged reveal that this differential T cell induction is not due to spike, as replacement of the A59 spike with that of JHM.SD (rA59/SJHM)" . _:b429914683 . _:b429914529 . _:b429914904 . _:b7430079 "Surprisingly, E is not an essential protein; however, a recombinant MHV lacking E expression replicates very inefficiently, consistent with the important role of E in production of infectious virus (Kuo and Masters >>2003<<). E proteins of several coronaviruses, including MHV, have been demonstrated to have ion channel activity (Wilson et al. 2006). While the role of this channel activity is unknown, it has been speculated to function at the site of budding" . . _:b429914907 . _:b429914886 . _:b429914906 . _:b429914917 . _:b429914916 . . _:b429914919 . _:b429914918 . _:b429914840 . _:b429914605 . _:b429914913 . _:b7429944 "SD or JHM-DL are so highly neurovirulent that most infected animals die from acute encephalitis, leaving few survivors with which to study the late demyelinating disease (Stohlman et al. >>1982<<; Ontiveros et al. 2003)." . _:b429914912 . _:b429914639 . _:b429914914 . _:b429914915 . . _:b429914914 . . _:b429914782 . _:b7429932 "1; Lai and Stohlman >>1978<<; Lee et al. 1991)." . . _:b7430172 "In studies using perforin-deficient mice, clearance of two JHM variants, the moderately virulent JHM-DM isolate (Stohlman et al. >>1998<<) and the neuroattenuated 2.2-V-1 isolate, was delayed compared to wild-type control mice, suggesting that perforin-mediated cytolysis contributes to, but is not required for, clearance of MHV from the CNS; furthermore, JHM-infected" . _:b429914921 . _:b7430180 "with the continued presence of viral RNA, suggesting that viral persistence (as evidenced by detection of viral RNA) provides a signal that is necessary to maintain these lymphocyte populations within the CNS (Marten et al. 2000a). Further studies using the glial-tropic JHM variant 2.2-V-1 revealed that CD8 T cells maintained in the CNS after viral clearance displayed a loss of ex vivo cytolytic activity while maintaining the ability to secrete IFN-\u03B3 (Bergmann et" . _:b7430085 . _:b429914920 . . . . _:b429914801 . _:b7430174 . _:b429914835 .