Toxoplasma gondii is a common food borne pathogen. It is estimated that 1.5 million people in the U.S. alone become infected with T. gondii annually and this protozoan parasite is the second most prevalent deadly foodborne pathogen in United States. Our studies comparing T. gondii infected gnotobiotic (germ-free) animals to conventional mice have established that the immunostimulatory signals induced by commensal bacteria have major effects on the outcomes of the parasitic infections. We also found that microbiota potentiates IFN-? responses and intestinal inflammation via the TLR adaptor protein MyD88. We hypothesize that synergistic innate sensing of microbiota and the parasite regulates the outcome of IFN-? dependent host resistance and immunopathology. We propose to build upon these findings to gain a mechanistic understanding of how innate recognition of microbiota influences IFN-? production during T. gondii infection, what cell types are involved in producing protective and immunopathological IFN-?, and the physiological consequences of T. gondii and microbiota-driven IFN-?. The proposed project is innovative because it examines a new way to think about host-parasite interactions in the presence of microbiota. It brings together a natural model for T. gondii infection, innate immune receptors involved in sensing parasite and microbiota, and mechanisms that regulate the production of IFN-? at the sites of infection.
In Aim 1, we will use mouse models and in vitro screening assays to identify innate immune sensors that regulate microbiota-dependent IFN-? production during T. gondii infection.
In Aim 2, we will determine cell type-specific contributions of innate and adaptive immune cells in IFN-?-dependent host defense and intestinal pathology.
In Aim 3, we will determine the impact of Paneth cells on T. gondii-induced intestinal pathogenesis by define biochemical pathways for T. gondii-induced Paneth cell death, and by defining the effects of Paneth cell loss on T. gondii-triggered intestinal pathogenesis using novel Paneth cell reporter and Paneth cell-deficient mice generated in our lab. These studies will advance our understanding of the protective and pathological effects of IFN-? during T. gondii infection.
Toxoplasma gondii is a common food borne pathogen and it is estimated that 1.5 million people in the U.S. alone become infected with T. gondii annually. The goal of this proposal is to explore how IFN-? production during T. gondii infection drives host defense and immunopathology.
