Tese de Doutorado
Breakdown of intestinal homeostasis by mucosal infections triggers adaptive immune responses against antigens from commensal bacteria
Fecha
2011-09-28Autor
Liliane Martins dos Santos
Institución
Resumen
The gastrointestinal tract of mammals is inhabited by thousands of distinct species of commensal microorganisms that exist in a mutualistic relationship with the host. It has previously been shown that these gut microbes play an important role in modulating host immune responses. On the other hand, commensals can also contribute to pathology in the context of acute infection. For instance, oral infections with Toxoplasma gondii in certain inbred strains of mice lead to an exacerbated intestinal inflammation that is accompanied by a loss of diversity within the gut flora. Furthermore, the microbiota was shown to aggravate the immunopathology of the disease. The mechanisms underlying this phenomenon still remain poorly understood. In order to study how the recognition of innocuous microbes can influence immune responses and pathological consequences during acute mucosal infections we treated mice a cocktail of antibiotics. Treated mice showed decreased inflammatory responses and lower parasite load. Germfree mice infected with T. gondii displayed less severe disorder with reduced parasite burden and lower levels of liver enzymes. Systemic translocation of gut bacteria was observed at the peak of infection in T. gondii-infectedmice as well as temporal changes in diversity of the gut microbial community. Three different bacteria that were abundant in the gut of T. gondii-infected mice at the peak of infection were isolated and used for investigation of specific immune responses against commensal bacteria. T. gondii acute infection induced specific antibody responsestowards antigens from the microbiota and adaptive cellular responses indicated by a strong DTH reaction against antigens from one of the isolated bacteria. Moreover, Moreover, CBir 1 TCR Tg cells that only respond to a specific peptide from flagellin become activated after oral infection with T. gondii. We also showed that antibody responses against the microbiota occur also after a less intense inflammatory responseinduced by Microsporidia infection or after Citrobacter rodentium colitis. Furthermore, vaccination of mice against E. coli led to a more efficient clearance of T. gondii parasites but did not worsen the immunopathology. All together our findings suggest that mucosal acute infections can trigger an adaptive immune response against gut commensals that in turn contributes to the protection of the host against subsequent infections.