Abstract
Inflammatory bowel disease (IBD) and Clostridium difficile infection cause gastrointestinal (GI) distension and, in severe cases, toxic megacolon with risk of perforation and death. Herpesviruses have been linked to severe GI dilatation. MHV-68 is a model for human gamma herpesvirus infection inducing GI dilatation in interleukin-10 (IL-10)-deficient mice but is benign in wildtype mice. MHV-68 also causes lethal vasculitis and pulmonary hemorrhage in interferon gamma receptor-deficient (IFNγR−/−) mice, but GI dilatation has not been reported. In prior work the Myxomavirus-derived anti-inflammatory serpin, Serp-1, improved survival, reducing vasculitis and pulmonary hemorrhage in MHV-68-infected IFNγR−/− mice with significantly increased IL-10. IL-10 has been investigated as treatment for GI dilatation with variable efficacy. We report here that MHV-68 infection produces severe GI dilatation with inflammation and gut wall degradation in 28% of INFγR-/- mice. Macrophage invasion and smooth muscle degradation were accompanied by decreased concentrations of T helper (Th2), B, monocyte, and dendritic cells. Plasma and spleen IL-10 were significantly reduced in mice with GI dilatation, while interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNFα) and INFγ increased. Treatment of gamma herpesvirus-infected mice with exogenous IL-10 prevents severe GI inflammation and dilatation, suggesting benefit for herpesvirus-induced dilatation.
Highlights
Murine gammaherpesvirus-68 (MHV-68) is a naturally occurring rodent pathogen that is closely related to Epstein-Barr virus (EBV), Kaposi’s sarcoma–associated herpesvirus (KSHV), and Herpesvirus saimiri 2 (HVS-2) [1,2,3]
MHV-68 infection causes a lethal sepsis in interferon gamma receptor-deficient (IFNγR−/− ) mice with large vessel vasculitis, pulmonary hemorrhage, and consolidation, while in wildtype (WT) mice MHV-68 produces a benign infection that can become latent [1,2,3,10,11,12,13,14]
We found that CD11b positive monocytes and F4/80 positive macrophage stainings were predominant and increased in the smooth muscle cells (SMC) layer in dilated gut sections (Figure 3A,B, CD11b staining; Figure 3C,D, F4/80 staining)
Summary
Murine gammaherpesvirus-68 (MHV-68) is a naturally occurring rodent pathogen that is closely related to Epstein-Barr virus (EBV), Kaposi’s sarcoma–associated herpesvirus (KSHV), and Herpesvirus saimiri 2 (HVS-2) [1,2,3]. Viruses 2018, 10, 518 from infectious mononucleosis and lymphoma to nasopharyngeal carcinoma and Kaposi’s sarcoma. Herpesviruses such as EBV and the beta herpesvirus, cytomegalovirus (CMV), are implicated in inflammatory bowel disease (IBD) [4,5,6,7,8,9]. Structurally the virus is more closely related to KSHV and HVS-2, MHV-68 pathogenesis in mice, in part, resembles that of EBV in humans
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