Cytomegalovirus infection aggravates intestinal inflammation during colitis and impairs the convalescence of the intestinal niche
PFEIFER K. 1, EBEL J. 1, TRILLING M. 2, LE-TRILLING V. 2, WESTENDORF A. 1
1 Institute of Medical Microbiology, University of Duisburg-Essen, University Hospital Essen, Essen, Germany; 2 Institute of Virology, University of Duisburg-Essen, University Hospital Essen, Essen, Germany
Human cytomegalovirus (HCMV) infection is ubiquitously prevalent in the global human population and has a high clinical relevance. After primary infection, the immune system of healthy individuals usually controls but never eliminates HCMV, resulting in lifelong latency, from which the virus frequently reactivates during episodes of stress or impaired immunity. In inflammatory bowel disease (IBD) patients, the prevalence of active HCMV replication is significantly increased and associated with more severe IBD manifestations. Since it is unclear how HCMV influences the disease progression in the intestinal tract, we established a model that combines a widely used colitis mouse model with mouse cytomegalovirus (MCMV) infection to elucidate the target cells of cytomegaloviruses (CMV) in the intestine and unravel how CMV affects gut inflammation.
In previously published studies, we found that an acute MCMV infection in BALB/c mice leads to high viral replication in colon tissue accompanied by an impaired intestinal barrier integrity and increased pro-inflammatory cytokine levels. Thus, CMV directly interferes with intestinal homeostasis, which might predispose for a stronger inflammation during colitis. To examine this, colitis was induced by dextran sodium sulfate (DSS) administration via the drinking water. Concomitantly, mice were infected with MCMV. Interestingly, infected mice exhibit aggravated colitis symptoms and a significantly reduced recovery compared to uninfected DSS-only control mice. Further analyses revealed that primary intestinal crypt cells represent direct targets of CMV infections. In addition, we observe a strong accumulation of activated CD8+ T-cells in colonic tissues of infected mice with colitis, which may also contribute to the stronger pathology.
Our results suggest a pathomechanism by which CMV infections aggravate inflammation in the gastrointestinal tract during colitis and impair the convalescence of the intestinal niche. Detailed understanding of the underlying pathophysiological mechanisms could accelerate the development of new treatment options for IBD patients with HCMV association.