The impact of primary and persistent cytomegalovirus infection on the progression of acute colitis in a murine model

Abstract

Cytomegalovirus (CMV) infects 60-100% of the population worldwide. CMV has been implicated in many diseases through the induction of inflammation. Inflammatory bowel disease (IBD) affects over 1 million Americans annually. IBD, in particular ulcerative colitis, has been associated with CMV infection. Here we use a murine model to test if both primary and persistent CMV infections exacerbate colitis. C57Bl/6J mice were injected with mock inoculum or murine CMV (mCMV) 4d (primary infection) or 6wks (persistent infection) before inducing colitis. Colitis was induced by administering 3% DSS (dextran sodium sulfate) in the drinking water for 6 days. Distilled water was given to controls. Disease activity index (DAI), derived from scores for stool consistency, body weight loss, occult blood, and rectal bleeding, was recorded daily. DAI increased early with DSS treatment in mocks when compared with water-treated controls. This was accelerated by both primary and persistent mCMV and appeared to be primarily due to the earlier appearance of gross bleeding versus their mock controls. Mocks reached similar DAI values by day 6. Myeloperoxidase was modestly elevated in the mCMV 4d-DSS over the mock 4d-DSS, however there was no such synergism in the 6 wk groups. Histology was comparable in mock and mCMV groups. Taken together our findings show that mCMV accelerated the development of acute colitis although a milder model of colitis may be needed to better delineate the impact of the virus on disease progression. Further work focusing on disruption of barrier function and bleeding may help determine the underlying mechanisms.

Animal models to study acute and chronic intestinal inflammation in mammals

“…Studies in immunocompromised NHP animal models and immunocompromised people with UC and CD demonstrate that intestinal inflammation and injury can be both induced [ 289 ] and exacerbated [ 24 , 290 , 291 ] following exposure to viral pathogens. Mouse models have also been used to facilitate acute colitis using cytomegalovirus to exacerbate DSS-induced colitis [ 292 ]. From the information described, it appears that a causal association between viral infections and the induction of intestinal inflammation in immunocompetent individuals remains undetermined.…”

Acute Cytomegalovirus Infection Modulates the Intestinal Microbiota and Targets Intestinal Epithelial Cells

“…Similarly, we observed HCMV positive intestinal epithelial cells in an IBD patient associated with HCMV, but the existence of a correlation/association does not necessarily inidcate causality. Nevertheless, CMV infection experiments in mouse models of IBD have shown that acute and latent CMV infection exacerbates intestinal inflammation [34][35][36][37].…”

“…Although the underlying mechanism are not entirely understood, it was demonstrated that concomitant MCMC infection increased gross bleeding [34], induced the production of proinflammatory cytokines or chemokine ligands in the colon [35,37], or stimulated gut immune responses to the gut microbiota [36].…”

“…Similarly, we observed HCMV positive intestinal epithelial cells in an IBD patient associated with HCMV, but the existence of a correlation/association does not necessarily inidcate causality. Nevertheless, CMV infection experiments in mouse models of IBD have shown that acute and latent CMV infection exacerbates intestinal inflammation [34–37]. Although the underlying mechanism are not entirely understood, it was demonstrated that concomitant MCMC infection increased gross bleeding [34], induced the production of pro-inflammatory cytokines or chemokine ligands in the colon [35, 37], or stimulated gut immune responses to the gut microbiota [36].…”

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

“…Similarly, we observed HCMV-positive intestinal epithelial cells in an IBD patient associated with HCMV, but the existence of a correlation/association does not necessarily indicate causality. Nevertheless, CMV infection experiments in mouse models of IBD have shown that acute and latent CMV infection exacerbates intestinal inflammation [35][36][37][38]. Although the underlying mechanism are not entirely understood, it was demonstrated that concomitant MCMV infection increased gross bleeding [35], induced the production of pro-inflammatory cytokines or chemokine ligands in the colon [36,38], or stimulated gut immune responses to the gut microbiota [37].…”