Department of Internal Medicine
Infectious Diseases Faculty
Fayyaz Sutterwala, M.D., Ph.D.
The innate immune system is the first line of defense against invading microorganisms. The focus of our studies is a recently described family of molecules called NLRs (NOD-like receptors) that have been demonstrated to be involved in the regulation of innate immune responses and cell death pathways. Some NLR family members have been shown to promote the activation of pro-inflammatory caspases within multiprotein complexes called inflammasomes. Mutations within NALP3, a member of the NLR family, have been linked to a group of autoinflammatory disorders in humans collectively known as the Cryopyrin-associated periodic syndromes. IPAF, another NLR family member, has been shown to play a crucial role in response to infection with a number of Gram-negative bacteria. To understand the role of NLRs in coordinating the immune response we have used a gene-targeting approach utilizing mice deficient in specific inflammasome components.
We are interested in three major areas of study.
- Characterizing the signaling events involved in activation of the NALP3- and IPAF-inflammasomes. This entails determining the specific ligand for NALP3 and IPAF and identifying downstream events mediated by their activation.
- Determining the role of NALP3 and IPAF in host the response to bacterial infection and identifying mechanisms pathogens use to evade these innate immune defenses.
- Characterizing the role of NLRs in murine models of autoimmune and autoinflammatory disease and correlating this to disease pathogenesis in humans.
- Sutterwala, F.S., L.A. Mijares, L. Li, Y. Ogura, B.I. Kazmierczak, and R.A. Flavell. 2007. Immune recognition of Pseudomonas aeruginosa is mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med. in press.
- Pedra, J.H., F.S. Sutterwala, B. Sukumaran, Y. Ogura, F. Qian, R.R. Montgomery, R.A. Flavell, and E. Fikrig. 2007. ASC/PYCARD and caspase-1 regulate the IL-18/IFNg axis during Anaplasma phagocytophilum infection. J. Immunol. 179:4783-4791.
- Sutterwala, F.S., Y. Ogura, and R.A. Flavell. 2007. The inflammasome in pathogen recognition and inflammation. J. Leukocyte Biol. 82:259-264.
- Sutterwala, F.S., Y. Ogura, M. Szczepanik, M. Lara-Tejero, G.S. Lichtenberger, E.P. Grant, J. Bertin, A.J. Coyle, J.E. Galán, P.W. Askenase, and R.A. Flavell. 2006. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 24:317-327.
- Lara-Tejero, M, F.S. Sutterwala, Y. Ogura, E.P. Grant, J. Bertin, A.J. Coyle, R.A. Flavell, and J.E. Galán. 2006. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203:1407-1412.
- Sutterwala, F.S., Y. Ogura, D.S. Zamboni, C.R. Roy, and R.A. Flavell. 2006. NALP3: a key player in caspase-1 activation. J. Endotoxin Res. 12:251-256.
- Ogura, Y., F.S. Sutterwala, and R.A. Flavell. 2006. The inflammasome: first line of the immune response to cell stress. Cell. 126:659-662
- Laouar, Y., F.S. Sutterwala, L. Gorelik, and R.A. Flavell. 2005. TGFb controls TH1 development through regulation of NK cell IFNg. Nat. Immunol. 6:600-607.
- Yarovinsky, F., D. Zhang, J.F. Andersen, G.L. Bannenberg, C.N. Serhan, M. S. Hayden, S. Hieny, F.S. Sutterwala, R.A. Flavell, S. Ghosh, and A. Sher. 2005. A profilin-like protein from Toxoplasma gondii potently triggers dendritic cell IL-12 production through TLR11. Science. 308:1626-1629.
Links of Interest