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Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells |
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| Authors: | Vu Thuy Khanh Le-Trilling Jana-Fabienne Ebel Franziska Baier Kerstin Wohlgemuth Kai Robin Pfeifer Aart Mookhoek Philippe Krebs Madita Determann Benjamin Katschinski Alexandra Adamczyk Erik Lange Robert Klopfleisch Christian M Lange Viktoriya Sokolova Mirko Trilling Astrid M Westendorf |
| Institution: | 1. Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;2. Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
contributed equally;3. Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;4. Institute of Pathology, University of Bern, Bern, Switzerland;5. Institute of Veterinary Pathology, Free University of Berlin, Berlin, Germany;6. Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;7. Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Inorganic Chemistry and Centre for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Essen, Germany |
| Abstract: | Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis. |
| Keywords: | cytomegalovirus colitis microbiota intestinal organoids epithelial cells |