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.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$829,124
Indirect Cost
City
State
Country
Zip Code
Linehan, Jonathan L; Harrison, Oliver J; Han, Seong-Ji et al. (2018) Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair. Cell 172:784-796.e18
Chen, Y Erin; Fischbach, Michael A; Belkaid, Yasmine (2018) Skin microbiota-host interactions. Nature 553:427-436
Byrd, Allyson L; Belkaid, Yasmine; Segre, Julia A (2018) The human skin microbiome. Nat Rev Microbiol 16:143-155
Ortiz, Alexandra M; Flynn, Jacob K; DiNapoli, Sarah R et al. (2018) Experimental microbial dysbiosis does not promote disease progression in SIV-infected macaques. Nat Med 24:1313-1316
Belkaid, Yasmine; Harrison, Oliver J (2017) Homeostatic Immunity and the Microbiota. Immunity 46:562-576
Collins, Nicholas; Belkaid, Yasmine (2017) Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens? Engaging Our Endogenous Adjuvants. Cold Spring Harb Perspect Biol :
Byrd, Allyson L; Deming, Clay; Cassidy, Sara K B et al. (2017) Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med 9:
Iwamura, Chiaki; Bouladoux, Nicolas; Belkaid, Yasmine et al. (2017) Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood 129:171-176
Chudnovskiy, Aleksey; Mortha, Arthur; Kana, Veronika et al. (2016) Host-Protozoan Interactions Protect from Mucosal Infections through Activation of the Inflammasome. Cell 167:444-456.e14
Hand, Timothy W; Vujkovic-Cvijin, Ivan; Ridaura, Vanessa K et al. (2016) Linking the Microbiota, Chronic Disease, and the Immune System. Trends Endocrinol Metab 27:831-843

Showing the most recent 10 out of 40 publications