Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R21ES033830&format=word)
Principal Investigator: Rockwell, Cheryl Elizabeth
Institute Receiving Award Michigan State University
Location East Lansing, MI
Grant Number R21ES033830
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 06 Sep 2022 to 31 Aug 2024
DESCRIPTION (provided by applicant): PROJECT SUMMARY Respiratory viruses, such as influenza, kill tens of thousands of people annually in the U.S. and worldwide, making it the eighth leading cause of death nationally. One of the perplexing aspects of this disease is the variability in interindividual response. Whereas many individuals experience manageable symptoms, others contract serious disease requiring hospitalization. While it is well established that NK cells are critical for early control of influenza infection, exciting new studies indicate that NK cells also provide an important memory response to influenza, a feature previously thought to be reserved for T cells and B cells. Our data indicate that a low dose of the synthetic food additive, tert-butylhydroquinone (tBHQ), impairs NK cell effector function and adversely impacts the innate immune response to influenza. Specifically, our recently published study shows that treatment of activated NK cells with tBHQ in vitro results in decreased induction of interferon-gamma (IFNγ), perforin and granzyme—all of which are critical molecules for controlling spread of viral infection within the host. Furthermore, our studies show that mice on a low-dose tBHQ diet have an impaired NK cell response to influenza as evidenced by a decreased percentage of IFNγ+ NK cells in the lung, decreased IFNγ gene expression and diminished induction of IFNγ and granzyme B. These effects precede an impaired T cell response to influenza, increased viral burden and worsened bronchostitial pneumonia, which is consistent with recent studies showing that the NK cell response is critical for optimal T cell activity in influenza. We have previously established that tBHQ is a potent and robust activator of Nrf2 in immune cells, which points to a possible mechanism for these effects. These preliminary data serve as the foundation for our central hypothesis, which is tBHQ diminishes NK cell effector function and memory through a Nrf2-dependent mechanism. We propose to test this hypothesis in two specific aims. Aim 1 is to determine the mechanism by which tBHQ inhibits NK cell activation and effector function. These studies will be conducted in wild-type and Nrf2-deficient models to determine the role of Nrf2 in these effects. We will also perform single-cell RNA- sequencing to determine the effect of tBHQ on functionally-distinct NK cell subsets. Aim 2 is to characterize the effect of tBHQ on the development of NK cell memory. This aim will utilize flow cytometry to identify memory NK cells and conditional knockout mice to determine the role of Nrf2 on the functionality of these cells.
Science Code(s)/Area of Science(s) Primary: 52 - Immunology/Immunotoxicology
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Michael Humble