Adaptations of the gastrointestinal tract to chronic viral infection
- Author(s): Labarta Bajo, Lara
- Advisor(s): Zuniga, Elina I
- et al.
Viral infections elicit host adaptations that can enable host-pathogen equilibrium. Here, we investigated adaptations of the gastrointestinal tract elicited by a persistent virus, their underlying mechanisms and their implications for the infected host. By using murine infection with lymphocytic choriomeningitis virus (LCMV) we demonstrated that infection with a persistent viral isolate led to long-term viral replication in hematopoietic and mesenchymal, but not epithelial cells (IEC) in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. IFN-I signaling caused tight junction dysregulation in IEC, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both IFN-I receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our results demonstrated that infection with a virus that persistently replicated in intestinal mucosa increased epithelial barrier permeability and revealed IFN-I and CD8 T cells as causative factors of intestinal leakage during chronic infections. We further discovered that mouse infection with the fast-spreading and persistent (but not the slow-spreading acute) isolate of LCMV induced large-scale microbiome shifts characterized by increased Verrucomicrobia and reduced Firmicute/Bacteroidetes ratio. Remarkably, the most profound microbiome changes occurred transiently after infection with the fast-spreading persistent isolate, were uncoupled from sustained viral loads and were instead largely caused by CD8 T cell responses and/or CD8-T-cell-induced anorexia. Among the taxa enriched by infection with the fast-spreading virus, Akkermansia muciniphila, broadly regarded as a beneficial commensal, bloomed upon starvation and in a CD8-T-cell-dependent manner. Strikingly, oral administration of Akkermansia muciniphila suppressed selected effector features of CD8 T cells in the context of both infections. Our findings define unique microbiome differences after chronic versus acute viral infections and identify CD8 T cell responses and downstream anorexia as driver mechanisms of microbial dysbiosis after infection with a fast-spreading virus. Our data also highlight potential context-dependent effects of probiotics and suggest a model in which changes in host behavior and downstream microbiome dysbiosis may constitute a previously unrecognized negative feedback loop that contributes to CD8 T cell adaptations after infections with fast-spreading and/or persistent pathogens.