Demyelinating and Nondemyelinating Strains of Mouse Hepatitis Virus Differ in Their Neural Cell Tropism (original) (raw)
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In vivo analysis of glial cell phenotypes during a viral demyelinating disease in mice
The Journal of Cell Biology, 1989
C57 BL/6N mice injected intracranially with the A59 strain of mouse hepatitis virus exhibit extensive viral replication in glial cells of the spinal cord and develop demyelinating lesions followed by virus clearing and remyelination. To study how different glial cell types are affected by the disease process, we combine three-color immunofluorescence labeling with tritiated thymidine autoradiography on 1-micron frozen sections of spinal cord. We use three different glial cell specific antibodies (a) to 2',3' cyclic-nucleotide 3' phosphohydrolase (CNP) expressed by oligodendrocytes, (b) to glial fibrillary acidic protein (GFAP) expressed by astrocytes, and (c) the O4 antibody which binds to O-2A progenitor cells in the rat. These progenitor cells, which give rise to oligodendrocytes and type 2 astrocytes and react with the O4 antibody in the adult central nervous system, were present but rare in the spinal cord of uninfected mice. In contrast, cells with the O-2A progenit...
2014
Neurotropic mouse hepatitis virus (MHV) is a member of the Coronavirus family induces hepatitis, meningitis, encephalitis, myelitis, neuritis, demyelination and axonal loss which mimics certain pathology of human neurological diseases multiple sclerosis (MS). Natural and genetically constructed recombinant MHV strains (generated by targeted RNA recombination) with differential pathological properties are used to understand the mechanisms of demyelination and concomitant axonal loss in a strain specific manner. These encompass both demyelinating (DM) and nondemyelinating (NDM) strains of MHVs, on which several comparative studies have been performed correlating the phenotypes, genomic sequences, and their pathogenicity. During acute infection, neurotropic DM strain infect a number of cell types in the CNS such as neurons, astrocytes, oligodendrocytes and microglia in the brain but in the spinal cord they preferentially infect neuron in the gray matter and oligodendrocytes and microgl...
Virology, 1995
Mice infected with the neurotropic JHM strain of mouse hepatitis virus (MHV-JHM) develop a demyelinating encephalomyelitis several weeks after infection. Astrogliosis and infiltration of inflammatory cells are prominent findings in the brains and spinal cords of infected mice. In this report, astrocytes in infected spinal cords were analyzed for expression of three pleiotropic cytokines, TNF-a, IL-1b, and IL-6; Type 2 nitric oxide synthase (iNOS); and MHC class I and II antigen. The data show that all three cytokines and iNOS are expressed by astrocytes in chronically infected spinal cords. These activated astrocytes are localized to areas of virus infection and demyelination, although most of the astrocytes expressing these proteins are not MHV-infected. MHC class I and II antigen can be detected in these spinal cords as well, but not in cells with the typical morphology of astrocytes. TNF-a, IL-6, and iNOS are also evident in the brains of mice with MHV-induced acute encephalitis, but in marked contrast to the results obtained with the chronically infected mice, most of the cells expressing these cytokines or iNOS had the morphology of macrophages or other mononuclear cells and very few appeared to be astrocytes. Additionally, astrocytes and, most likely, oligodendrocytes are infected in the spinal cords of mice with chronic demyelination. These results are consistent with a role for both viral infection of glial cells and high localized levels of proinflammatory cytokines and nitric oxide in the demyelinating process in mice infected with MHV-JHM. They also show that analogously to the human demyelinating disease, multiple sclerosis, astrocytes are a major cellular source for these cytokines in mice with chronic, but not acute disease.
Immunologic Research, 2007
Infection of mice with variants of mouse hepatitis virus, strain JHM (MHV-JHM), provide models of acute and chronic viral infection of the central nervous system (CNS). Through targeted recombination and reverse genetic manipulation, studies of infection with MHV-JHM variants have identified phenotypic differences and examined the effects of these differences on viral pathogenesis and anti-viral host immune responses. Studies employing recombinant viruses with a modified spike (S) glycoprotein of MHV-JHM have identified the S gene as a major determinant of neurovirulence. However, the association of S gene variation and neurovirulence with host ability to generate anti-viral CD8 T cell responses is not completely clear. Partially protective anti-viral immune responses may result in persistent infection and chronic demyelinating disease characterized by myelin removal from axons of the CNS and associated with dense macrophage/ microglial infiltration. Demyelinating disease during MHV-JHM infection is immunemediated, as mice that lack T lymphocytes fail to develop disease despite succumbing to encephalitis with high levels of infectious virus in the CNS. However, the presence of T lymphocytes or anti-viral antibody can induce disease in infected immunodeficient mice. The mechanisms by which these immune effectors induce demyelination share an ability to activate and recruit macrophages and microglia, thus increasing the putative role of these cells in myelin destruction.
Differential Astrocyte Response to Theiler’s Murine Encephalomyelitis Virus Infection
Intervirology, 2005
Objectives: We aimed to address if selective astrocyte apoptosis is involved in the lack of murine demyelinating disease following infection by the L*-1 variant of Theiler’s virus. In addition, we investigated whether L*-1-infected astrocytes were able to selectively express molecules whose effects would play a role as pathogenic factors. Methods: Murine cultured astrocytes were infected with two Theiler viruses, the DA strain and the mutated DA variant L*-1, which does not synthesize the out of frame L* protein. Results: Neither DA nor L*-1 provoked apoptosis, although they replicated in astrocytes inducing GFAP and iNOS expression, as well as subsequent nitric oxide production. In addition, both viruses caused an enhanced expression of ICAM-1, VCAM-1 and decay accelerating factor (DAF). In this connection, values of VCAM-1 and DAF induced by L*-1 were higher and lower, respectively, than those induced by DA. Conclusions: Since no apoptosis was found, such mechanism would not be in...
Acute and Persistent Viral Infections of Differentiated Nerve Cells
Clinical Infectious Diseases, 1982
Within the nervous system the highly specialized structure and function of nerve cells renders the pathogenesis of viral infections amazingly complex. In vivo and in vitro studies reveal that viruses may display tropism for distinct types of cells such as neurons, myelin-forming cells, or astrocytes. In neurons, RNA viruses mature in the cell body and in dendrites close to synapses, from which they can spread to synaptic endings. Undefined host factors and stage of differentiation may favor defective viral assembly, which, in turn, results in persistent infections of neurons. In myelin-forming cells, lytic infection results in degeneration of myelin and, consequently, in altered conduction in those axons that are ensheathed by a myelin-forming cell. In addition, breakdown of myelin may induce an autoimmune response, which then leads to further demyelination. Autoimmune demyelination may also occur when glial cells other than myelin-forming cells are infected. Astrocytes are prone to persistent infection or viral transformation.
Virology, 2004
Differences in disease outcome between the highly neurovirulent MHV-JHM and mildly neurovirulent MHV-A59 have been attributed to variations within the spike (S) glycoprotein. Previously, we found that MHV-JHM neurovirulence was marked by diminished expression of interferon-gamma (IFN-gamma) mRNA and a reduced presence of CD8 T cells in the CNS concomitant with heightened macrophage inflammatory protein (MIP)-1 transcript levels and greater macrophage infiltration relative to MHV-A59 infection. Here, the ability of the S and non-spike genes to regulate these immune responses was evaluated using chimeric viruses. Chimeric viruses WTR13 and S4R22 were made on MHV-A59 variant backgrounds and, respectively, contained the S gene of MHV-A59 and MHV-JHM. Unexpectedly, genes other than S appeared to modulate events critical to viral replication and survival. Unlike unresolving MHV-JHM infections, the clearance of WTR13 and S4R22 infections coincided with strong IFN-gamma transcription and an increase in the number of CD8 T cells infiltrating into the CNS. However, despite the absence of detectable viral titers, approximately 40% of S4R22-infected mice succumbed within 3 weeks, indicating that the enhanced mortality following S4R22 infection was not associated with high viral titers. Instead, similar to the MHV-JHM infection, reduced survival following S4R22 infection was observed in the presence of elevated MIP-1alpha and MIP-1beta mRNA accumulation and enhanced macrophage numbers within infected brains. These observations suggest that the S protein of MHV-JHM influences neurovirulence through the induction of MIP-1alpha- and MIP-1beta-driven macrophage immunopathology.
Journal of Neuroimmunology, 1981
Demyelinadon may be induced by several different pathogenetic mechanisms. We have been utilizing mouse hepatitis virus (MHV) t o study virus-induced demyalination in the central net'vous system (CNS). To learn whether the different disease phenotypes in 4-week-old mice caused by wild type (a modal for fatal encephalomyditis) or mutaf.t 158 (a model for primary demyelination), is due to an altered cellular tropism, we have developed an immnnolabeling technique to evaluate critically the localization of MHV antigens in the unique ceils of the CNS. Using mouse derived L-cells and primar.~ neuronal cells in vitro, we determined an appropriate fixative (4% paraformaldehyde and 0.5% glutaraldehyde) that both preserved MHV antigenicity and cell structure. These studies in vitro showed the presence of MHV antigens on the surface of cells.