The role of gamma interferon in infection of susceptible mice with murine coronavirus, MHV-JHM (original) (raw)
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Immunobiology, 1992
The possible role of interferon-gamma (IFN-y) in the resistance of A/J mice to MHV3 infection was investigated. Monoclonal antibodies specific for IFN-y, CD4 and CDS molecules were administered in vivo to deplete selectively the IFN-y synthesized or the appropriate subset of T cells. The animals were then infected with MHV3 and the course of infection was followed by studying different parameters, such as, the mortality, the virus growth in the tissues and the IFN-y synthesis in sera and peritoneal exudates. After MHV3 infection, a full resistance of control A/J mice was observed, in contrast to the high mortality rate observed among the depleted animals, where higher virus titers were found in different tissues. The IFN-y synthesis in sera and peritoneal exudates of depleted mice, after MHV3 infection, drastically decreased when compared to that detected in control mice. The data presented are consistent with the hypothesis that IFN-y plays an essential role in the resistance of A/J mice to MHV3 infection.
Inhibition of the Alpha/Beta Interferon Response by Mouse Hepatitis Virus at Multiple Levels
Journal of Virology, 2007
Mouse hepatitis virus (MHV) was used as a model to study the interaction of coronaviruses with the alpha/beta interferon (IFN-α/β) response. While MHV strain A59 appeared to induce IFN-β gene transcription and low levels of nuclear translocation of the IFN-β transcription factor interferon regulatory factor 3 (IRF-3), MHV did not induce IFN-β protein production during the course of infection in L2 mouse fibroblast cells. In addition, MHV was able to significantly decrease the level of IFN-β protein induced by both Newcastle disease virus (NDV) and Sendai virus infections, without targeting it for proteasomal degradation and without altering the nuclear translocation of IRF-3 or IFN-β mRNA production or stability. These results indicate that MHV infection causes an inhibition of IFN-β production at a posttranscriptional level, without altering RNA or protein stability. In contrast, MHV induced IFN-β mRNA and protein production in the brains of infected animals, suggesting that the in...
Mouse hepatitis virus (MHV) is a singular name for a group of murine coronaviruses that cause a wide spectrum of clinical outcomes ranging from subclinical infection to enteritis, hepatitis, and encephalitis. Enterotropic MHV strains, such as MHV-Y, initially replicate in epithelial cells of the gastrointestinal (GI) tract after infection of adult immunocompetent mice. Disease is acute and mild with minimal pathologic changes, and virus rarely disseminates to other organs (1-3). In contrast, morbidity and mortality are high in neonatal immunocompetent mice, and infection of immunocompromised mice can cause multisystemic, persistent infection with extended viral shedding (4) and high mortality (5). Polytropic MHV strains, such as MHV-A59 or MHV-JHM, initially replicate in the proximal respiratory tract epithelium after infection, then disseminate to many organs via viremia, lymphatic spread, or olfactory pathways from the nose to the brain. Infection of adult immunocompetent mice results in subclinical infection, hepatitis, and/or encephalitis (6), whereas infection of immunocompromised mice can cause severe disseminated disease with high mortality.
Acute hepatic failure in IFN-γ-deficient BALB/c mice after murine coronavirus infection
Virus Research, 2002
We previously showed that an intraperitoneal infection with mouse hepatitis virus (MHV) persists in interferon-g (IFN-g)-deficient C57BL/6 (B6-GKO) mice and results in subacute fatal peritonitis, which bears a resemblance to feline infectious peritonitis. To examine the role of other host factors in MHV infection in mice, IFN-g-deficient mice with a BALB/c background (BALB-GKO) were infected intraperitoneally with MHV and compared with B6-GKO mice. In contrast to B6-GKO mice, BALB-GKO mice died within 1 week due to acute hepatic failure. The viral titer of the liver in BALB-GKO mice was significantly higher than that in B6-GKO mice. All hepatocytes in BALB-GKO mice were necrotic at 5 days post-infection, which was clearly distinct from large but limited lesion in the liver from infected B6-GKO mice. The serum alanine aminotransferase activity of infected BALB-GKO mice were higher than that of B6-GKO mice and was paralleled with the severity of the pathological changes and viral titers in infected mice. Administration of exogenous IFN-g to BALB-GKO partially inhibited the acute death. These results indicate that BALB-GKO and B6-GKO mice clearly show different diseases following MHV infection, although wild type counterparts of both mice apparently showed the same clinical course after MHV infection.
Cell-Type-Specific Type I Interferon Antagonism Influences Organ Tropism of Murine Coronavirus
Journal of Virology, 2011
Previous studies have demonstrated that mouse hepatitis virus (MHV) hepatotropism is determined largely by postentry events rather than by availability of the viral receptor. In addition, mutation of MHV nonstructural protein 2 (ns2) abrogates the ability of the virus to replicate in the liver and induce hepatitis but does not affect replication in the central nervous system (CNS). Here we show that replication of ns2 mutant viruses is attenuated in bone marrow-derived macrophages (BMM) generated from wild-type (wt) mice but not in L2 fibroblasts, primary astrocytes, or BMM generated from type I interferon receptor-deficient (IFNAR −/− ) mice. In addition, ns2 mutants are more sensitive than wt virus to pretreatment of BMM, but not L2 fibroblasts or primary astrocytes, with alpha/beta interferon (IFN-α/β). The ns2 mutants induced similar levels of IFN-α/β in wt and IFNAR −/− BMM, indicating that ns2 expression has no effect on the induction of IFN but rather that it antagonizes a la...
Murine Coronavirus Cell Type Dependent Interaction with the Type I Interferon Response
Viruses, 2009
Coronaviruses infect many species of animal including humans, causing acute and chronic diseases of many organ systems. Murine coronavirus, mouse hepatitis virus (MHV) infection of the mouse, provides animal models for the study of central nervous system disease, including encephalitis and demyelinating diseases such as Multiple Sclerosis and for hepatitis. While there are many studies of the adaptive immune response to MHV, there has until recently been scant information on the type I interferon (IFN) response to MHV. The relationship between MHV and the IFN-α/β response is paradoxical. While the type I IFN response is a crucial aspect of host defense against MHV in its natural host, there is little if any induction of IFN following infection of mouse fibroblast cell lines in vitro. Furthermore, MHV is relatively resistant to the antiviral effects of IFN-α/β in mouse fibroblast cell lines and in human 293T cells. MHV can, under some circumstances, compromise the antiviral effects of IFN signaling. The nucleocapsid protein as well as the nsp1 and nsp3 proteins of MHV has been reported to have IFN antagonist activity. However, in primary cell types such as plasmacytoid dendritic cells (pDC) and macrophages, IFN is induced by MHV infection and an antiviral state is established. Other primary cell types such as neurons, astrocytes and hepatocytes fail to produce IFN following infection and, in vivo, likely depend on IFN produced by pDCs and macrophages for protection from MHV. Thus MHV induction of IFN-α/β and the ability to induce an antiviral state in response to interferon is extremely cell type dependent. IFN induced protection from MHV pathogenesis likely requires the OPEN ACCESS Viruses 2009, 1 690 orchestrated activities of several cell types, however, the cell types involved in limiting MHV replication may be different in the liver and in the immune privileged CNS.
Murine Coronavirus Delays Expression of a Subset of Interferon-Stimulated Genes
Journal of Virology, 2010
The importance of the type I interferon (IFN-I) system in limiting coronavirus replication and dissemination has been unequivocally demonstrated by rapid lethality following infection of mice lacking the alpha/beta IFN (IFN-α/β) receptor with mouse hepatitis virus (MHV), a murine coronavirus. Interestingly, MHV has a cell-type-dependent ability to resist the antiviral effects of IFN-α/β. In primary bone-marrow-derived macrophages and mouse embryonic fibroblasts, MHV replication was significantly reduced by the IFN-α/β-induced antiviral state, whereas IFN treatment of cell lines (L2 and 293T) has only minor effects on replication (K. M. Rose and S. R. Weiss, Viruses 1:689-712, 2009). Replication of other RNA viruses, including Theiler's murine encephalitis virus (TMEV), vesicular stomatitis virus (VSV), Sindbis virus, Newcastle disease virus (NDV), and Sendai virus (SeV), was significantly inhibited in L2 cells treated with IFN-α/β, and MHV had the ability to rescue only SeV repl...
Journal of General Virology, 1988
Treatment of Wag/Rij rats with recombinant rat interferon gamma (rRIF-y) resulted in complete protection against a lethal pseudorabies virus (PRV) infection. To investigate whether the protection resulted from direct inhibition of virus replication or from a stimulation of immune mechanisms, we tested rRIF-7 activity in naturally immunocompromised and artificially immunosuppressed rats. The antiviral effect of rRIF-7 was not abolished in silica-and carrageenan-treated, phagocyte-depleted rats. Immunologically immature newborn and T cell-deficient nude rats were also protected under a regime of rRIF-7 treatment as well as whole body gamma-irradiated rats. Sera of the protected rats were devoid of PRV-neutralizing antibodies. Our results indicate that the protective activity of rRIF-y is based on direct inhibition of virus replication; stimulation of the immune system is not required but may be responsible for protection upon challenge several weeks after infection. 0000-8184 © 1988 SGM Downloaded from www.microbiologyresearch.org by IP: 54.162.190.106 On: Tue, 23 Feb 2016 09:53:43 1980 v.E.C.J. SCHIJNS AND OTHERS METHODS
Journal of General Virology, 2009
Gamma interferon (IFN-γ) plays a major role in the protection against lethal infection with mouse hepatitis virus A59. IFN-γ production reaches a maximum level 2 days after viral inoculation, especially in liver immune cells. Among these cells, natural killer cells are the major producers of this cytokine. Transfer experiments indicated that the protective role of IFN-γ is mediated through a direct effect on cells targeted by the virus rather than through indirect activation of T lymphocytes.