CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-10, Vol.117 (40), p.24998-25007
• Main Authors: Labarta-Bajo, Lara, Gramalla-Schmitz, Anna, Gerner, Romana R., Kazane, Katelynn R., Humphrey, Gregory, Schwartz, Tara, Sanders, Karenina, Swafford, Austin, Knight, Rob, Raffatellu, Manuela, Zúñiga, Elina I.
• Format: Article
• Language: English
• Subjects: Adaptation; Akkermansia; Animals; Anorexia; Anorexia - immunology; Anorexia - microbiology; Anorexia - virology; Biological Sciences; CD8 antigen; CD8 Antigens - immunology; CD8 Antigens - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - microbiology; Context; Dysbacteriosis; Dysbiosis - immunology; Dysbiosis - microbiology; Dysbiosis - virology; Eating disorders; Feedback loops; Firmicutes - immunology; Firmicutes - metabolism; Gastrointestinal Microbiome - immunology; Humans; Immune system; Immunologic Memory - immunology; Immunological tolerance; Infections; Intestine; Lymphocytes; Lymphocytes T; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - microbiology; Lymphocytic Choriomeningitis - pathology; Lymphocytic choriomeningitis virus - pathogenicity; Mice; Microbiomes; Microorganisms; Negative feedback; Oral administration; Pathogens; Probiotics; Spreading; T-Lymphocytes - immunology; T-Lymphocytes - microbiology; Verrucomicrobia - immunology; Verrucomicrobia - pathogenicity; Viral infections; Virus Diseases - immunology; Virus Diseases - microbiology; Virus Diseases - pathology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2003656117

Infections elicit immune adaptations to enable pathogen resistance and/or tolerance and are associated with compositional shifts of the intestinal microbiome. However, a comprehensive understanding of how infections with pathogens that exhibit distinct capability to spread and/or persist differentially change the microbiome, the underlying mechanisms, and the relative contribution of individual commensal species to immune cell adaptations is still lacking. Here, we discovered that mouse infection with a fast-spreading and persistent (but not a slow-spreading acute) isolate of lymphocytic choriomeningitis virus 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 A. 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 infectionwith a fast-spreading virus. Our data also highlight potential context-dependent effects of probiotics and suggest amodel 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 fastspreading and/or persistent pathogens.