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 mediate the protective TLR-independent effects of IFN-?.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI121090-04
Application #
9645589
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Lapham, Cheryl K
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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
López-Yglesias, Américo H; Burger, Elise; Araujo, Alessandra et al. (2018) T-bet-independent Th1 response induces intestinal immunopathology during Toxoplasma gondii infection. Mucosal Immunol 11:921-931
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