Pathogenesis of acute and chronic central nervous system infection with variants of mouse hepatitis virus, strain JHM

Abstract

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 immune-mediated, 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.

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

“…A third method, the adoptive transfer of T cells isolated from myelin peptide primed animals, allows the selection or in vitro manipulation of T cells before transfer to naive recipients to produce EAE (Robinson et al, 2014). Another inflammatory model of demyelination utilizes viruses- Theiler's murine encephalomyelitis virus (TMEV), or neurotrophic variants of the mouse hepatitis virus (MHV) - that stimulate the activity of T cells to induce chronic demyelination (Lane and Buchmeier, 1997; Templeton and Perlman, 2007). Immune mediators secreted by T cells and macrophages/microglia have been suggested to contribute to virally-induced demyelination due to dysregulation or death of oligodendrocyte lineage cells (Marro et al, 2014).…”

In Vivo Potential Effects of Adenovirus Type 5 E1A and E1B on Lung Carcinogenesis and Lymphoproliferative Inflammation

“…However, previous studies implied that the persistent presence of viral proteins and their alternatively upregulated growth cytokines may be responsible for the lung LPL seen in the lungs of transgenic mice (3,4,18,21,24). Recent studies indicate that some cytokines, such as interleukin-6 and interleukin-15, acting as lymphocyte survival or inflammatory factors, have a fundamental role in homeostatic proliferation and inflammatory filtration (5,10).…”

Role of IFN-γ responsiveness in CD8 T cell-mediated viral clearance and demyelination in coronavirus-infected mice

“…The neurotropic mouse hepatitis virus, strain JHM (MHV-JHM) is a well-studied pathogen that upsets the balance between viral clearance and regulation of host immune responses in the CNS Perlman and Dandekar, 2005;Stohlman et al, 1998;Templeton and Perlman, 2007). MHV-JHM is a member of the family coronaviridae, which includes pathogens that are responsible for an array of human diseases ranging in pathogenicity from the relatively innocuous common cold to the more damaging severe acute respiratory syndrome (SARS).…”