: Worldwide, toxoplasmosis and other infections caused by obligate intracellular parasitic agents remain a major cause of morbidity and mortality in humans and in livestock. A central mediator of host defense against these agents is IFN-gamma, a cytokine produced by Type 1 lymphocytes and NK cells. Toxoplasma gondii infection in the mouse represents a well-characterized model to study the differentiation of type 1 cells and a highly stringent test to assess IFN-gamma function in vivo. This proposal will systematically define the intercellular and intracellular signals that govern the prompt initiation, maintenance and successful functioning of IFN-gamma-mediated responses critical for host survival. The experimental methods rely on in vivo infection and genetic studies of normal and defective mouse strains aided by ex vivo cellular and molecular analyses of lymphocyte function.
The first aim will critically assess the lymphocyte cell lineage and transcription factor requirements for IL-12 induced, IFN-gamma mediated host resistance to T. gondii infection.
The second aim evaluates the role of Tbet, a novel Thi -specific transcription factor in sustaining long term IFN-gamma effector function and thus immune protection. A final third aim will provide detailed phenotypic and genetic analyses of a newly discovered defect in early IL-12 induced IFN-gamma responses resulting in acute susceptibility to T. gondii infection. The influence of this genetically dictated, partial lL-12 unresponsiveness on signal transduction and transcription factor(s) pathways critical for IFN-gamma production will be evaluated. The proposed experiments should provide novel information on cellular and molecular regulatory determinant(s) affecting the generation, maintenance and appropriate functioning of IFN-gamma producing type 1 lymphocytes during a successful and balanced immune response. Since many infectious and autoimmune pathologies result from Type 1 effector dysfunction, the insights provided by the proposed studies should eventually result in improved management of such disease states. This grant should also provide insights for designing immunization strategies to induce sustained type 1 responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050618-05
Application #
7061712
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Wali, Tonu M
Project Start
2002-06-01
Project End
2007-08-31
Budget Start
2006-06-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2006
Total Cost
$219,544
Indirect Cost
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Wilson, Douglas C; Matthews, Suzanne; Yap, George S (2008) IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection. J Immunol 180:5935-45
Zhao, Yanlin; Wilson, Douglas; Matthews, Suzanne et al. (2007) Rapid elimination of Toxoplasma gondii by gamma interferon-primed mouse macrophages is independent of CD40 signaling. Infect Immun 75:4799-803
Gaddi, Pamela J; Yap, George S (2007) Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol 85:155-9
Shaw, Michael H; Freeman, Gordon J; Scott, Mark F et al. (2006) Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation. J Immunol 176:7263-71
Ling, Yun M; Shaw, Michael H; Ayala, Carol et al. (2006) Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J Exp Med 203:2063-71
Yap, George S; Shaw, Michael H; Ling, Yun et al. (2006) Genetic analysis of host resistance to intracellular pathogens: lessons from studies of Toxoplasma gondii infection. Microbes Infect 8:1174-8
Shaw, Michael H; Boyartchuk, Victor; Wong, Sandy et al. (2003) A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc Natl Acad Sci U S A 100:11594-9
Yap, George S; Sher, Alan (2002) The use of germ line-mutated mice in understanding host-pathogen interactions. Cell Microbiol 4:627-34