Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating disease multiple sclerosis. The contributions of CD4 ؉ and CD8 ؉ T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4؊/؊ mice than in CD8 ؊/؊ and C57BL/6 mice (P < 0.002 and P < 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4؊/؊ mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8 ؊/؊ and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4 ؊/؊ mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P < 0.001) compared to those in control mice. These data indicate that CD4 ؉ T cells have a pivotal role in accelerating CNS inflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.Demyelination is a complex neuropathological process in which the myelin sheath that insulates and protects axons is damaged or destroyed. Several animal models of demyelination have been developed that have provided valuable contributions to the understanding of the immunopathological events that may drive human demyelinating diseases such as multiple sclerosis (MS) (22,31). Among these is the neurotropic mouse hepatitis virus (MHV) model of virus-induced demyelination (12,18). MHV is a positive-strand RNA virus that causes a variety of clinical diseases in susceptible strains of mice (23). Neurovirulent strains of MHV cause an acute encephalomyelitis that may ultimately progress to demyelinating disease characterized clinically by abnormal gait and hind-limb paralysis. Histologically, affected animals exhibit mononuclear cell infiltration and myelin destruction. Early studies suggested that the demyelination observed in MHV-infected mice was the result of virus-induced damage or destruction of oligodendrocytes (9, 36). However, more recent reports have indicated that MHV-induced demyelination is more complex and may also involve immunopathologic responses against viral antigens expressed in infected tissues (5, 35).As T cells are considered central to the development of demyelinating lesions in animal models of demyelination as well as MS, it is imperative to better understand the mechanisms by which these cells exert their pathological effect (24, 25). We sought to evaluate the contributions of CD4 ϩ and CD8 ϩ T cells in MHV-induced central nervous system (CNS) d...
Hybrids of tobacco mosaic virus (TMV) were constructed with the use of fusion to the coat protein peptides of 10 or 15 amino acids, containing the 5B19 epitope from the spike protein of murine hepatitis virus (MHV) and giving rise to TMV-5B19 and TMV-5B19L, respectively. The TMV hybrids were propagated in tobacco plants, and the virus particles were purified. Immunogold labeling, with the use of the monoclonal MAb5B19 antibody, showed specific decoration of hybrid TMV particles, confirming the expression and display of the MHV epitope on the surface of the TMV. Mice were immunized with purified hybrid viruses after several regimens of immunization. Mice that received TMV-5B19L intranasally developed serum IgG and IgA specific for the 5B19 epitope and for the TMV coat protein. Hybrid TMV-5B19, administered by subcutaneous injections, elicited high titers of serum IgG that was specific for the 5B19 epitope and for coat protein, but IgA that was specific against 5B19 was not observed. Mice that were immunized with hybrid virus by subcutaneous or intranasal routes of administration survived challenge with a lethal dose (10 ؋ LD 50 ) of MHV strain JHM, whereas mice administered wild-type TMV died 10 d post challenge. Furthermore, there was a positive correlation between the dose of administered immunogen and protection against MHV infection. These studies show that TMV can be an effective vaccine delivery vehicle for parenteral and mucosal immunization and for protection from challenge with viral infection.Several plant viruses have been developed for use as vectors for the expression and delivery of foreign peptides (1-7). These examples include immunogenic epitopes that can be used in vaccines to confer protective immunity against human and animal diseases. We have demonstrated that a hybrid tobacco mosaic virus (TMV), containing the 13 amino acid sequence of the murine zona pellucida ZP3 epitope fused to a region near the C terminus of the coat protein (CP) successfully elicited the production of anti-ZP3 antibody in parenterally immunized animals. Anti-ZP3 antibody accumulated around the ova of immunized animals; however, it did not prevent fertilization (5).Murine hepatitis virus (MHV), a member of the Coronaviridae family, is responsible for a variety of acute and chronic diseases in its natural host. The strain JHM of MHV induces demyelinating encephalomyelitis with high mortality, and surviving mice exhibit chronic demyelination. MHV contains at least three dominant structural proteins: the membrane glycoprotein (M protein), the nucleocapsid protein (N protein), and the spike glycoprotein (S protein) (8). The S protein is posttranslationally processed to yield the S1 and the S2 proteins (9). The S protein has been the focus of many studies because of its important role in viral attachment to target cellular receptors (10), its membrane penetration, and its ability to induce cell fusion (11). The S protein is a critical determinant of viral pathogenicity and has been shown to contain major immunodomina...
Intranasal inoculation of the neuroattenuated OBLV60 strain of mouse hepatitis virus results in infection of mitral neurons in the olfactory bulb, followed by spread along olfactory and limbic pathways to the brain. Immunocompetent BALB/c mice were able to clear virus by 11 days postinfection (p.i.). Gamma interferon (IFN-␥) may play a role in clearance of OBLV60 from infected immunocompetent BALB/c mice through a nonlytic mechanism. Among the variety of immunomodulatory activities of IFN-␥ is the induction of expression of inducible nitric oxide synthase (iNOS), an enzyme responsible for the production of nitric oxide (NO). Studies were undertaken to investigate the role of IFN-␥ and NO in host defense and clearance of OBLV60 from the central nervous system (CNS). Exposure of OBLV60-infected OBL21a cells, a mouse neuronal cell line, to the NO-generating compound S-nitroso-L-acetyl penicillamine resulted in a significant decrease in viral replication, indicating that NO interfered with viral replication. Furthermore, infection of IFN-␥ knockout (GKO) mice and athymic nude mice with OBLV60 resulted in low-level expression of iNOS mRNA and protein in the brains compared to that of OBLV60-infected BALB/c mice. Nude mice were unable to clear virus and eventually died between days 11 and 14 p.i. (B. D.
A cardinal feature of the biology of lymphocytic choriomeningitis virus (LCMV) is its ability to establish persistent infections in mice. Persistence is usually established by infection of the mouse during the in utero or neonatal period. Susceptibility can be extended to the adult by treatment with immunosuppressive agents or by infection with immunosuppressive strains of LCMV. In this study we investigated the capacity of passively acquired anti-LCMV antibodies to prevent the establishment of persistence in both neonatal and adult mice. Suckling BALB/c mouse pups nursed by mothers immunized against LCMV before pregnancy had higher survival rates following infection than controls and withstood challenge doses of up to 400 PFU without becoming persistently infected. To establish that maternal antibody alone and not maternally derived T cells provided this protection, nonimmune mothers were infused with monoclonal anti-LCMV neutralizing antibodies within 24 h after delivering their pups. Pups nursing on these passively immunized mothers were resistant to persistent LCMV infection. The establishment of persistence in adult BALB/c mice by the immunosuppressive, macrophage-tropic LCMV variant, clone 13 was also prevented by prophylactic treatment with anti-LCMV monoclonal antibodies. However, the protection afforded by passively acquired antibody was found to be incomplete if the recipients lacked functional CD8 ؉ T cells. While 65% of neonatal athymic (nu/nu) mice nursed by immune nu/؉ dams resisted low-dose viral challenge (25 PFU), the majority of nude pups challenged with high doses of virus (100 PFU) became persistently infected. Also, protection was incomplete in  2-microglobulin knockout mice, which lack functional CD8 ؉ T cells, suggesting that a cooperative effect was exerted by the combination of neutralizing antibody and endogenous T cells. These results indicate that antibodies provide an effective barrier to the establishment of persistent infections in immunocompetent mice and reaffirm that vaccines which induce strong humoral responses may provide efficient protection against arenavirus infections.
Infection of C57BL/6 mice with the V5A13.1 strain of mouse hepatitis virus (MHV-V5A13.1) results in an acute encephalomyelitis and chronic demyelinating disease with features similar to the human demyelinating disease multiple sclerosis. Chemokines are a family of proinflammatory cytokines associated with inflammatory pathology in various diseases. The kinetics and histologic localization of chemokine production in the central nervous system of MHV-infected mice were examined to identify chemokines that contribute to inflammation and demyelination. Transcripts for the chemokines cytokine-response gene-2 (CRG-2), regulated on activation, normal T cell expressed and secreted (RANTES), macrophage-chemoattractant protein-1 and protein-3 (MCP-1, MCP-3), macrophage-inflammatory protein-1β (MIP-1β), and MIP-2 were detected in the brains of MHV-infected mice at 3 days postinfection (p.i.), and these transcripts were increased markedly in brains and spinal cords at day 7 p.i., which coincides with the occurrence of acute viral encephalomyelitis. By day 35 p.i., RANTES, CRG-2, and MIP-1β were detected in brains and spinal cords of mice with chronic demyelination. CRG-2 mRNA expression colocalized with viral RNA and was associated with demyelinating lesions. Astrocytes were the predominant cell type expressing CRG-2 mRNA. These observations suggest a role for chemokines, notably CRG-2, in the initiation and maintenance of an inflammatory response following infection with MHV, which is important in contributing to demyelination.
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