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, 3- the pathogenesis of mucosal or dermal infections is highly controlled by the nature of the microbiota present at the time of infection and 4- that acute infections lead to the induction of memory responses against commensals.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$858,001
Indirect Cost
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Belkaid, Yasmine; Tamoutounour, Samira (2016) The influence of skin microorganisms on cutaneous immunity. Nat Rev Immunol 16:353-66
Naik, Shruti; Bouladoux, Nicolas; Linehan, Jonathan L et al. (2015) Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520:104-8
Ridaura, Vanessa; Belkaid, Yasmine (2015) Gut microbiota: the link to your second brain. Cell 161:193-4
Nakamizo, Satoshi; Egawa, Gyohei; Honda, Tetsuya et al. (2015) Commensal bacteria and cutaneous immunity. Semin Immunopathol 37:73-80
Fonseca, Denise Morais da; Hand, Timothy W; Han, Seong-Ji et al. (2015) Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity. Cell 163:354-66
Shen, Wei; Li, Wenqing; Hixon, Julie A et al. (2014) Adaptive immunity to murine skin commensals. Proc Natl Acad Sci U S A 111:E2977-86
Belkaid, Yasmine; Segre, Julia A (2014) Dialogue between skin microbiota and immunity. Science 346:954-9
Mortha, Arthur; Chudnovskiy, Aleksey; Hashimoto, Daigo et al. (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288
Gros, Philippe; Belkaid, Yasmine (2014) Editorial overview: Host pathogens. Curr Opin Immunol 29:iv-vi
Grainger, John R; Wohlfert, Elizabeth A; Fuss, Ivan J et al. (2013) Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat Med 19:713-21

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