T-bet-regulated myeloid innate defense against Toxoplasma gondii

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Abstract Toxoplasma gondii is the causative agent of toxoplasmosis, and it is estimated to infect a third of the human population globally. T. gondii infection can result in serious complications including congenital toxoplasmosis of the fetus and death among immunocompromised individuals. Unfortunately, current regimens for T. gondii treatment show high rates of toxicity, and are only able to treat the acute stage of the parasitic infection. Therefore, there is an urgent need develop new medicines with specific efficacy against T. gondii. Host immunity against T. gondii is defined by a MyD88-dependent IL-12 response, which generates a CD4+ Th1- derived IFN-γ response necessary for host survival. The transcription factor T-bet is considered essential for the development and function of innate lymphoid cells (ILCs) and TH1s during T. gondii infection. T-bet is traditionally considered the master regulator of lymphocyte-derived interferon-gamma (IFN-γ) production. Yet, T-bet-independent ILC- and TH1-derived IFN-γ is insufficient for host immunity, demonstrating that IFN-γ alone is insufficient for host defense and that T-bet must be inducing an IFN-γ-independent anti-parasitic response. For instance, despite robust IFN-γ production, T-bet-deficient mice succumb to infection significantly faster than animals lacking lymphocytes, suggesting T-bet-expressing myeloid cells are required for host survival. Our objective is to define T-bet’s role in regulating myeloid cell-dependent immunity against T. gondii. Our preliminary findings have identified a unique T-bet expressing CD11c+MHCII- myeloid cell population that are critical for eliminating T. gondii. Based on these results, we hypothesize that T-bet expression in myeloid cells regulates pathogen clearance and host survival during T. gondii infection. To test our hypothesis, we will (i) determine the underlying mechanism(s) of T-bet in regulating myeloid cell-mediated defense against T. gondii (AIM 1) and (ii) define the molecular functions of T-bet-expressing myeloid cells in mediating host resistance against T. gondii (AIM 2). We will utilize unbiased T-bet reporter mice and cell-type-specific T-bet-deficient mice established in our lab, in combination with various molecular biology techniques, spectral cytometry, immunofluorescence, and single-cell RNA-sequencing. Together, these experiments will for the first time establish T-bet’s role in mediating myeloid cell-dependent host defense against T. gondii, thereby providing novel specific targets for therapeutic intervention.