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. These studies will advance our understanding of how human and mouse innate immune systems
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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| Burger, Elise; Araujo, Alessandra; López-Yglesias, Américo et al. (2018) Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation. Cell Host Microbe 23:177-190.e4 |
| Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8 |
