Cytomegalovirus modulates acute colitis and impairs the resolution of inflammatory processes

Human cytomegalovirus (HCMV) is an opportunistic pathogen that is ubiquitously present in the human population and implicated in numerous inflammatory processes within the body. The virus is a leading cause of morbidity and mortality in immunocompromised individuals, causing severe end organ diseases such as HCMV colitis. In patients with inflammatory bowel disease (IBD), the prevalence of active intestinal HCMV replication is significantly increased and associated with exacerbated disease progression. However, the underlying pathomechanism by which an intestinal HCMV manifestation affects both the intestine under homeostatic conditions and the inflammatory processes during an acute colitis remains to be elucidated. The present study aims to investigate to which extent a CMV infection affects the intestinal milieu. In immunocompetent BALB/c mice a mouse CMV (MCMV) infection established a robust viral replication in the colonic tissue. Consequently, a mild pro-inflammatory milieu was induced mediated by alterations in the secretion of TNFα, IFNγ and granzyme B. Furthermore, the viral replication induced apoptosis in the intestinal epithelium, and thereby, compromised the barrier integrity and disrupted the homeostatic conditions in the colon. To further assess the consequences of the viral replication on acute intestinal inflammation, mice were infected during the course of dextran sodium sulfate (DSS)-induced colitis. Consistent with the findings in IBD patients, the viral infection aggravated the inflammatory processes during acute colitis and impaired the subsequent resolution of intestinal inflammation compared to uninfected colitis mice. During the recovery phase, the MCMV infection induced the accumulation of pro-inflammatory innate and adaptive immune cells in the colonic lamina propria. Notably, the presence of cytotoxic CD8+ T cells contributed to the intestinal inflammatory processes. The depletion of these pro-inflammatory T cells resulted in a tremendous amelioration of colitis and enhancement of intestinal inflammatory resolution. Furthermore, the compromised recovery phenotype of the infected mice was further mediated by the functional impairment of the intestinal stem cells (ISCs), which were demonstrated to be susceptible to MCMV. Subsequent RNA sequencing analysis of infected ISCs indicated a wide array of differently expressed genes mediating severe metabolic changes for the multipotent stem cells. Moreover, the infected ISCs exhibited a significantly increased expression of chemokines, thereby orchestrating the demonstrated accumulation of the pro-inflammatory immune cells in the gut. Finally, vaccination with the ΔM27-MCMV live-attenuated virus demonstrated robust protection against a challenge MCMV infection during acute colitis, emphasising the urgent need for the development of a potent human CMV vaccine in the context of IBD. In conclusion, this study provides new insight into the pathomechanism by which CMV affects the inflammatory processes in the gut during acute colitis.