Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology (original) (raw)
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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 regulation of innate and adaptive immune responses in viral encephalitis
Virology, 2004
Viral encephalitis is a global health concern. The ability of a virus to modulate the immune response can have a pivotal effect on the course of disease and the fate of the infected host. In this study, we sought to understand the immunological basis for the fatal encephalitis following infection with the murine coronavirus, mouse hepatitis virus (MHV)-JHM, in contrast with the more attenuated MHV-A59. Distinct glial cell cytokine and chemokine response patterns were observed within 3 days after infection, became progressively more polarized during the course of infection and with the infiltration of leukocytes. In the brain, MHV-JHM infection induced strong accumulation of IFNbeta mRNA relative to IFNgamma mRNA. This trend was reversed in MHV-A59 infection and was accompanied by increased CD8 T cell infiltration into brain compared to MHV-JHM infection. Increased apoptosis appeared to contribute to the diminished presence of CD8 T cells in MHV-JHM-infected brain with the consequence of a lower potential for IFNgamma production and antiviral activity. MHV-JHM infection also induced sustained mRNA accumulation of the innate immune response products interleukin (IL)-6 and IL-1. Furthermore, high levels of macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta, and MIP-2 mRNA were observed at the onset of MHV-JHM infection and correlated with a marked elevation in the number of macrophages in the brain on day 7 compared to MHV-A59 infection. These observations indicate that differences in the severity of viral encephalitis may reflect the differential ability of viruses to stimulate innate immune responses within the CNS and subsequently the character of infiltrating leukocyte populations.
Journal of Neuroimmunology, 1991
The eradication of infectious virus from the central nervous system (CNS) following infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) is thought to be immune-mediated. Furthermore, a significant decrease of infectious virus coincides with the appearance of prominent inflammatory infiltrates in the brain and spinal cord. In the present study, mononuclear cells infiltrating the brain during JHMV infection were isolated and characterized. While all subsets of immune cells were present, there appeared to be a temporal relationship between the peak incidence of CD8 ÷ T cells (40% of total isolated cells) and reduction of virus at day 7 post-infection. Cells with the natural killer (NK) phenotype (at least 30%) were also present throughout infection. These data suggest that CD8 ÷ T cells and NK cells are prominent among cells which infiltrate the brain during JHM virus infection and may have important roles in reduction of virus within the CNS.
The Journal of …, 2009
Persistence of even the stealthiest viruses can perturb immune function either to the benefit or detriment of the host. Lymphocytic choriomeningitis virus (LCMV) establishes lifelong, systemic persistence when introduced in utero or at birth. Despite a highly evolved host-pathogen relationship, LCMV cannot escape detection by the innate immune system, which results in chronic stimulation of the type 1 IFN pathway in adult carrier mice. In this study we demonstrate that IFN- is chronically up-regulated in peripheral lymphoid and nonlymphoid tissues (but not the CNS) of mice persistently infected from birth with LCMV and that dendritic cells (DCs) represent at least one source of IFN-. Interestingly, chronic stimulation of this innate pathway significantly elevated MHC class I expression in the CNS as well as the periphery. Elevated MHC I expression was dependent on IFN-␣ receptor but not MyD88-dependent signaling, as only genetic deletion of the former reduced MHC I to normal levels. An increase in circulating virus was also observed in the IFN-␣ receptor deficient carrier mice, signifying that type I IFN continually exerts anti-viral pressure during a LCMV carrier state. Finally, to determine whether heightened CNS MHC I could be therapeutically corrected, we purged LCMV carrier mice of their persistent infection using adoptive immunotherapy. This treatment significantly reduced CNS MHC I expression. Collectively, these data demonstrate that even a well adapted pathogen can chronically stimulate the innate immune system and consequently alter the expression of Ag presenting machinery in an immunologically specialized compartment like the CNS.
Mouse Hepatitis Virus Infection Upregulates Genes Involved in Innate Immune Responses
PLoS ONE, 2014
Neurotropic recombinant strain of Mouse Hepatitis Virus, RSA59, induces meningo-encephalitis, myelitis and demyelination following intracranial inoculation. RSA59 induced neuropathology is partially caused by activation of CNS resident microglia, as demonstrated by changes in cellular morphology and increased expression of a microglia/macrophage specific calcium ion binding factor, Iba1. Affymetrix Microarray analysis for mRNA expression data reveals expression of inflammatory mediators that are known to be released by activated microglia. Microglia-specific cell surface molecules, including CD11b, CD74, CD52 and CD68, are significantly upregulated in contrast to CD4, CD8 and CD19. Protein analysis of spinal cord extracts taken from mice 6 days post-inoculation, the time of peak inflammation, reveals robust expression of IFN-c, IL-12 and mKC. Data suggest that activated microglia and inflammatory mediators contribute to a local CNS microenvironment that regulates viral replication and IFN-c production during the acute phase of infection, which in turn can cause phagolysosome maturation and phagocytosis of the myelin sheath, leading to demyelination.
Virology, 2001
The protein encoded by ORF 4 of mouse hepatitis virus (MHV) is not required for growth of some strains in tissue culture cells, but its role in pathogenesis in the murine host has not been defined previously in a controlled manner. MHV strain JHM causes acute and chronic neurological diseases in susceptible strains of rodents. To genetically manipulate the structural proteins of this and other strains of MHV, we have generalized an interspecies-targeted RNA recombination selection that was originally developed for the A59 strain of MHV. Using this approach, a recombinant MHV-JHM was constructed in which gene 4 was genetically inactivated. Virus lacking gene 4 expression replicated in tissue culture cells with similar kinetics to recombinant virus in which gene 4 expression was not disrupted. Both types of viruses exhibited similar virulence when analyzed in a murine model of encephalitis. These results establish a targeted recombination system for inserting mutations into MHV-JHM. Furthermore, the protein encoded by ORF 4 is not essential for growth in tissue culture cells or in the CNS of the infected host.
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...
Microbial Pathogenesis, 1987
The presence of maternal antibodies protected suckling C57BL/6 mice from the clinical manifestations of the acute encephalomyelitis caused by mouse hepatitis virus, strain JHM (MHV-JHM), a coronavirus, even though histological evidence of encephalomyelitis was found at early times after inoculation. 100% of infected suckling mice developed a fatal disease in the absence of maternal antibody. By 14 days after inoculation, the brains of all antibody-protected mice examined were nearly normal on histological examination. At 3-8 weeks post-inoculation, approximately 40% of the antibody-protected mice developed a neurological disease characterized by hindlimb paralysis and wasting. Evidence of inflammation and demyelination was apparent in the spinal cord and brainstem. The mice that remained asymptomatic at this time showed few signs of inflammation and none developed clinical disease over the following 9 months. Viral antigen could be detected in most of the mice examined at all times after inoculation, whether symptomatic or not, and was particularly evident in the animals with hindlimb paralysis. MHV-JHM could be consistently cultured from the mice with hindlimb paralysis. These results show that maternal immune factors can completely protect susceptible mice from the acute, fatal, clinical encephalomyelitis caused by MHV-JHM, but cannot prevent the establishment of a latent state and subsequent development of virus-induced, clinically evident, demyelinating disease. This model will be useful for studying the virus and host factors important for the development of MHV-JHM latency and subsequent virus-induced demyelination .