IFN-? is a key cytokine that mediates host resistance to a variety of intracellular pathogen. Until recently, it was largely acknowledged that lymphoid cells are the sole sources for IFN-?. We have recently established that neutrophils are an emerging cellular source of IFN-?, a key cytokine that mediates host defense to Toxoplasma gondii and other intracellular pathogens. Production of IFN-? by neutrophils, in contrast to lymphoid cells, is Toll-like receptor (TLR) and IL-12-independent and the events associated with IFN-? production by neutrophils are not understood. We have also observed that neutrophils express IFN-? during their lineage development in the bone marrow niche independently of microbes. IFN-? accumulates in neutrophilic granules and is released upon induction of neutrophil degranulation. We propose to build upon these findings to gain a deeper understanding of how neutrophil-derived IFN-? expression is regulated, and to investigate the physiological significance of neutrophil-derived IFN-? in mouse and human models of toxoplasmosis.
In Aim 1, we will identify neutrophil precursors involved in IFN-? production in nave and Toxoplasma gondii-infected mice and determine the transcription factors that regulate IFN-? production in human and mouse neutrophil.
In Aim 2, we will use mice harboring neutrophil-specific IFN-? deficiency to test the hypothesis that neutrophil-derived IFN-? coordinates innate and adaptive immune responses to Toxoplasma gondii. Our goal is to determine protective mechanisms mediated by neutrophil-derived IFN-? in vivo. These studies will advance our understanding of how human and mouse innate immune systems mediate the protective TLR-independent effects of IFN-?.
The goal of this proposal is to explore a newly identified mechanism of intracellular pathogen control by neutrophils secreting IFN-?, a key cytokine required for host resistance to the infection. Our findings should yield novel strategies for enhancing immunity to a broad range of intracellular pathogens.
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