Role of Gut and Skin Flora in the Control of Immune Responses

National Institute Of Allergy And Infectious Diseases

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Abstract

Mammalian barrier surfaces host complex microbial communities whose combined membership outnumbers our own cells by at least a factor of ten. Recent studies have highlighted the fundamental role of these microbes in the maintenance of host homeostasis. For instances, commensals can play a major role in the control of host defense, metabolism and tissue development. This symbiotic relationship however bears a constant threat to the host. In the gut in particular, reactivity against intestinal flora poses a substantial risk that can lead to severe tissue damage. Thus, sites exposed to commensals must be able to tolerate constant exposure to innocuous antigens while maintaining the capacity to rapidly respond to encounters with pathogens. These conflicting pressures confront the host immune system defending the GI tract with a unique challenge. Our work explores how the microflora controls pathogen expansion as well as their immunopathologic consequences. To address these issues, we are focusing our research on the dermal parasite (Leishmania major) and gastrointestinal pathogens, Cryptosporidium and Microsporidium and Toxoplasma spp. In particular, we are exploring 1- the mechanisms by which regulatory T cells are induced or manipulated in the context of exposure to food antigen, commensals or pathogens 2- we are assessing the function of the microbiota or microbiota derived signals in pathogenesis and 3- we are evaluating the role of the microbiota in the control of effector responses against cutaneous and mucosal infections. Our work reveals that 1- the microbiota is required for appropriate control of skin and gastrointestinal infection and that the mechanisms by which commensals control both sites are distinct;2- defined microbial products such as bacterial DNA play a dominant role in the control of these responses and 3- the pathogenesis of mucosal or dermal infections is highly controlled by the nature of the microbiota present at the time of infection.