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RESEARCH SUMMARY
Our major research goal is to define the cellular and molecular pathways required for successful immune responses against intracellular pathogens. This entails a balance between responses that suppress the growth and survival of invading pathogens and those that prevent destruction of host tissues. The murine model of Toxoplasma gondii infection provides a useful paradigm for these studies. Host survival and immunity to this cosmopolitan protozoan parasite is dependent on activation of effector cells by interferon-gamma and tumor necrosis factor-alpha produced by T lymphocytes activated during the course of infection. In addition, IL-10 plays a critical role in down-regulating the inflammatory response and minimizing immunopathology. We are addressing two fundamental questions:
1. What are the intracellular molecular mediators of cytokine-induced protective responses?
2. How are the lymphocytes that produce these protective cytokines generated and regulated?
We utilize modern approaches, including gene mapping of susceptibility traits, immunologic analyses of transgenic and knockout mice, biochemical analysis of signal transduction pathways and cell imaging of the host-parasite interaction. Our efforts have led to the discovery of a novel molecular defect in the IL-12 host resistance pathway and an understanding of the in vivo protective and regulatory functions of signaling molecules (Tyk2), and transcription factors (Tbet) expressed by Th1 lymphocytes. We have recently discovered a new regulatory circuit that controls the balance between pro-inflammatory and anti-inflammatory responses to infection. We are also actively characterizing the mechanisms of intracellular inactivation of toxoplasms by cytokine activated effector cells, involving iNOS, IGTP and other IFN-gamma regulated enzymes.
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PUBLICATIONS
Yap, G. S. and A. Sher. Effector cells of both non-hemopoietic and hemopoietic origin are required for interferon-g and tumor necrosis factor-a dependent host resistance to Toxoplasma gondii. J. Exp. Med. 189:1083-1091, 1999.
Reis e Souza, C.*, Yap, G.*, Schulz, O., Roger, N., Schito, M., Aliberti, J., Hieny, S., and A. Sher. 1999. Paralysis of dendritic cell IL-12 production by microbial products prevents infection induced immunopathology. Immunity 11:627-647. (* Equivalent contribution from authors)
Schaeffer, E. M., Debnath, J., Yap, G., McVicar, D., Sher, A., Varmus, H. E., Lenardo, M. J., and P. L. Schwartzberg. 1999. Requirements for Tec kinases in T cell receptor signaling and immunity. Science 284:638-641.
Collazo, C.M., G.S. Yap, Sempowski, G.D., Lusby, K.C., Tessarollo, L., VandeWoude, G.,Sher, A., and G.A., Taylor. 2001. Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection. J. Exp. Med. 194:181-187.
Jankovic, D. J., A. Sher and G. S. Yap. 2001. Th1/Th2 effector choice in parasitic infection: decision making by committee. Curr. Opin. Immunol. 13:403-409.
Schaeffer, E.M. *, Yap, G. S. *, Czar, M. J., Lewis, C. M., McVicar, D., Cheever, A., Sher, A., and P. L. Schwartzberg. 2001. Mutation of Tec family kinases alters T helper differentiation: Evidence for a Th2 bias in hyporesponsive cells. Nature Immunol. 2:1183-1188. (* Equivalent contribution from authors)
Yap, G. S. and A. Sher. 2002. The use of germline mutated mice in understanding host-pathogen interactions. Cell. Microbiol. 4:627-634.
Shaw, M., Boyartchuk, V., Wong, S., Kashioghoff, M., Ragimbeau, J., Pellegrini, S., Muller, M., Dietrich, W., and G. S. Yap. 2003. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infectious and autoimmune disease. Proc. Natl. Acad. Sci. 100: 11594-11599.
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LAB MEMBERS
 From left - Yanlin Zhao, George Yap, Douglas Wilson, Suzanne Matthews, Pamela Gaddi
George Yap, Assistant Professor
Yanlin Zhao, Postdoctoral Research Associate
Suzanne Matthews, Research Assistant
Pamela Gaddi, Pathobiology Graduate Student
Douglas Wilson, Pathobiology Graduate Student
Manuela Belda, Undergraduate Student |
