Natural killer (NK) cells constitute an important arm of the host immune system that detects and eliminates virus-infected cells. Newborns and immunocompromised patients lack NK cells and are extremely susceptible to viral infection, and in particular, human cytomegalovirus (HCMV) can cause severe health complications or be life-threatening in these individuals. Mouse cytomegalovirus (MCMV) is an accurate and robust model for HCMV infection, and represents a good system to study antiviral NK cell responses. Using MCMV infection in mice, we have discovered that NK cells possess novel adaptive immune features such as clonal expansion and long-lived memory. From the funding in the initial R01 period, our lab has uncovered many of the cellular and molecular mechanisms underlying NK cell memory. Our long-term goals are to understand the general biology of NK cells and the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion. To this end, we have recently identified a novel role for the transcription factor IRF8 in the NK cell response against MCMV infection. Based on this exciting preliminary data, our current R01 renewal proposes to use a newly-generated transgenic mouse where Irf8 is specifically ablated in NK cells to study the impact of this transcription factor in antiviral responses.
In Aim 1, we will perform epigenetic profiling of activated NK cells to determine how IRF8-mediated NK cell expansion and effector function are controlled following MCMV infection.
In Aim 2, we will identify the binding partners and gene targets of IRF8 in antiviral NK cells using proteomic and transcriptomic analyses, respectively.
In Aim 3, we will measure mitochondrial health and metabolism in antiviral NK cells to investigate the mechanisms behind IRF8-mediated survival of effector and memory NK cells during the contraction phase following MCMV clearance. Together, the studies in this R01 renewal will not only advance our understanding of the transcriptional mechanisms whereby NK cells contribute to host defense during viral infection, but also establish novel clinical paradigms for how the NK cell compartment may be harnessed for immunization and therapeutic strategies against infectious disease.

Public Health Relevance

Cytomegalovirus can cause serious health problems and life-threatening disease in newborns and immune-suppressed individuals (including cancer and transplant patients). This proposal seeks to understand the transcriptional regulation underlying the natural killer (NK) cell-mediated control of viral infection. Defining the molecular mechanisms by which NK cells respond to pathogens will potentially lead to therapeutic benefits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI100874-06
Application #
9382454
Study Section
Immunity and Host Defense (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2012-06-18
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Madera, Sharline; Rapp, Moritz; Firth, Matthew A et al. (2016) Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J Exp Med 213:225-33
O'Sullivan, Timothy E; Rapp, Moritz; Fan, Xiying et al. (2016) Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance. Immunity 45:428-41

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