Immune responses and cytokine induction in the development of severe hepatitis during acute infections with murine cytomegalovirus

Abstract

Salivary gland-derived murine cytomegalovirus (SGV) infections of mice have been widely used as models of human cytomegalovirus infections and in the study of CMV biology. Still, many aspects of SGV pathogenesis are not clearly defined. Fatal and non-fatal SGV infections were investigated to characterize pathogenetic correlates of mortality and to assess the role of the immune response in disease progression. Suppression of immune responses was observed in both lethal and sublethal infections. Depletion of immune cell populations in spleen, however, correlated with severe CMV-induced hepatitis and mortality. In addition, T cell depletion studies indicated a requirement for this immune cell subset in control of liver damage and survival of infected mice. Examination of cytokine responses revealed a previously undescribed shock-like syndrome in lethally-infected mice characterized by high levels of tumor necrosis factor alpha and interferon gamma. Furthermore, the sites of tumor necrosis factor alpha gene induction did not strictly correlate with either viral load or the sites of tissue damage during infection. Taken together, these findings define the pathogenetic progression of disease as it relates to disease outcome and suggests that organ-specific differences in cytokine induction play a significant role in the late stages of acute lethal MCMV infections.

CXCR3-Dependent Recruitment of Antigen-Specific T Lymphocytes to the Liver during Murine Cytomegalovirus Infection

“…Additional studies have demonstrated that CD8 T cells accumulate in the liver following infection with MCMV (12,19,20,48,51); however, this is the first report documenting the mechanisms required for promoting their recruitment and that of MCMV-specific CD8 T cells. Our results show a clear induction of CXCL9 and CXCL10 protein in the liver during MCMV infection.…”

“…It is speculated that CXCL9 induction reflects the innate NK cell-mediated IFN-␥ effects (37,40,41,43,50), as this chemokine is highly dependent on IFN-␥ for production (53,56). However, CXCL10 can be in- duced by IFN-␥ in addition to other molecules, including tumor necrosis factor alpha, which is found in the liver during MCMV infection (20,33,36,51). In addition, as antibody neutralization of these CXCR3 ligands reduced the proportions and total numbers of hepatic MCMV-specific CD8 T cells, it is probable that the combined effects of these chemokines initiate the CD8 T-cell inflammatory response but CXCL10 may exert distinct functions during late acute MCMV infection in the liver that remain to be determined.…”

“…Previous studies have demonstrated that immunocompetent C57BL/6 mice establish viral clearance and resolution of virus-induced liver disease between 5 and 7 days of MCMV infection (12,14,41,42,51). To specifically evaluate the effects of CXCR3 responses on overall liver function, expression of the liver enzyme ALT was measured in serum samples from CXCR3 ϩ/ϩ and CXCR3 Ϫ/Ϫ mice that were uninfected or infected with MCMV for 5 or 7 days.…”

“…In the liver, adoptive transfer of MCMVprimed CD8 T cells into ␥-irradiated hosts leads to effective control of viral replication and specifically limits the extent of liver pathology (38,39). Additionally, T-cell depletion studies demonstrated a role for these cells in controlling hepatic damage and promoting host survival (34,51), suggesting that the MCMV-infected liver is sensitive to immune control by CD8 T cells. Furthermore, studies have demonstrated the accumulation and development of an effective CD8 T-cell response in various tissues that becomes maximally apparent 7 days after infection with MCMV (12,20).…”

Genetic control of innate immune responses against cytomegalovirus: MCMV meets its match

“…Infection of mice with MCMV mimics virus-induced disease in humans in terms of presenting a large spectrum of clinical manifestations. For example, high viral titres in target organs are associated with pneumonitis, 50 hepatitis 51 and retinitis. 52,53 Moreover high viral titres in the spleen or liver may lead to fatal infection.…”