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1、34910.2217/FVL.12.23 2012 Future Medicine Ltd ISSN 1746-0794Future Virol. (2012) 7(4), 349359 Future Virology part of Mouse hepatitis virus (MHV) is a large (3032 kb), enveloped ssRNA virus that is a member of the Coronaviridae family in the order Nidovirales 1. These viruses include a variety of st
2、rains that can induce wide-ranging patholo- gies dependent on age, strain and route of infec- tion. Examples include the hepatotropic MHV-2 strain which leads to fulminant hepatitis follow- ing intraperitoneal (ip.) injection, but is weakly neurotropic, causing only mild acute meningitis following i
3、ntracranial (ic.) inoculation 2. By contrast, ic. infection of susceptible mice with the dual neurotropic and hepatotropic A59 strain results in infection of neurons and glial cells within the CNS, resulting in a mild encephalo- myelitis, limited demyelination and hepatitis 3,4. The JHM strain of MH
4、V (JHMV), a well- characterized laboratory strain that was initially serially passaged in suckling mouse brains to produce a highly neurovirulent virus, can cause severe encephalomyelitis and demyelination in adult mice 5. Infection of susceptible mice with neuroattenuated variants of JHMV have yiel
5、ded useful surrogate mouse models for: nViral-induced encephalomyelitis; nDefining molecular mechanisms governing neuroinflammation; nCharacterizing mechanisms associated with viral-induced immune-mediated demyelina- tion; nDeveloping novel approaches to promote remyelination within the context of p
6、ersistent viral infection of the CNS. JHMV-induced acute encephalomyelitis Following a sublethal ic. infection with the neuroadapted JHMV, the virus infects and replicates within ependymal cells lining the lat- eral ventricles 6. Within 24 h, JHMV rapidly spreads and penetrates further into the pare
7、n- chyma, where astrocytes, oligodendrocytes and microglia are targets of infection 6,7. The virus also disseminates to the spinal cord through cerebrospinal fluid, targeting ependymal cells prior to spreading to glial cells of the white matter tracts 6. Viral titers within the brain peak between da
8、ys 57 postinfection (p.i.) and decline below levels of detection by plaque assay (100 PFU/g tissue) between 1014 days p.i. 8. However, clearance is incomplete and viral antigens and RNA are capable of persist- ing within the CNS 9, and this is associated with chronic neuroinflammation leading to an
9、immune-mediated demyelinating disease with CXCR2 signaling and host defense following coronavirus-induced encephalomyelitis Brett S Marro1, Martin P Hosking1,2 viral RNA and antigens persist and are sequestered primarily within white matter tracts, and this is accom- panied by the presence of activa
10、ted glial cells and retention of virus-specific CD4+ and CD8+ T cells 8,9,48. Neutralizing JHMV-specific anti- body is detected during chronic disease and is critical in preventing viral recrudescence 4951. More recently, Perlman and colleagues have provided important insight into the functional rol
11、e of Tregs during acute JHMV-induced CNS disease 52,53. Tregs are detected within the CNS at the same time as effector CD4+ T cells, indi- cating that the emergence and accumulation of both populations of cells is on a similar timeline following viral infection. Furthermore, virus- specific Tregs ex
12、press both IFN-g and IL-10, suggesting that they have immune regulatory properties that are mediated, in part, by cyto- kines secreted following antigen stimulation. Indeed, virus-specific Tregs dampen prolifera- tion of virus-specific effector CD4+ T cells, and depletion of Tregs increases mortalit
13、y 52,53. These data suggest that within the context of acute JHMV-induced neurological disease, Tregs limit immunopathological disease without negatively impacting viral clearance 52. JHMV-induced demyelination A hallmark feature of JHMV infection of the CNS occurs following the acute stage of disea
14、se, in which the virus has spread into the spinal cord where it infects astrocytes and oligoden- droglia. As a result, the virus persists as non- infectious RNA and animals develop demyelin- ating lesions within the brain and spinal cord that are associated with clinical manifestations including awk
15、ward gait and hindlimb paralysis. Current evidence suggests that demyelination in JHMV-infected mice is not the result of epitope spreading and induction of an immune response against neuroantigens, as has recently been reported to occur during Theilers virus-induced demyelination 54,55. However, ad
16、optive trans- fer of T cells from JHMV-infected rats to naive recipients results in demyelination 56. Whether a similar response occurs in MHV-infected mice and what the contributions are to demyelination are unknown at this time. A recent report has suggested that infection with MHV strain A59 promotes the activation of autoreactive T cells specific to myelin basic protein, although the contributions of these cells to demyelination are undefined 57. Oligodendrocytes are an important vir
