Impaired NK cell function by the synthetic food additive tBHQ

合成食品添加剂 tBHQ 损害 NK 细胞功能

基本信息

批准号：
10698142
负责人：
Elizabeth M. Gardner
金额：
$ 22.68万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-06 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698142
关键词：
2-tert-butylhydroquinone Activated Natural Killer Cell Address Affect Allergens B-Lymphocytes Cause of Death Cell physiology Cells Chemicals Consumption Contracts Data Development Diet Disease Dose Effector Cell Flow Cytometry Food Food Additives Food Industry Foundations Gene Expression Goals Granzyme Hospitalization Human Immune Immune response Immunity Impairment In Vitro Individual Influenza Influenza A Virus, H1N1 Subtype Influenza vaccination Innate Immune Response Interferon Type II Knockout Mice Knowledge Label Literature Lung Memory Modeling Morbidity - disease rate Mus NK Cell Activation Natural Killer Cells Nature Persons Pneumonia Process Publishing Regulatory Pathway Research Role Safety Source Stress Symptoms T cell response T-Lymphocyte Testing Time Toxic effect United States Food and Drug Administration Vaccination Viral Viral Load result Virus Diseases Xenobiotics antiviral immunity cell type chemical safety conditional knockout cytokine cytotoxicity experience exposed human population food consumption future pandemic immune function immunotoxicity in vivo individual response influenza infection insight mortality novel pathogen perforin respiratory virus response single-cell RNA sequencing transcription factor

项目摘要

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.

项目概要流感等呼吸道病毒每年在美国和世界范围内夺去数万人的生命，使其成为全国第八大死亡原因。尽管许多人的症状是可以控制的，但其他人的反应却存在差异。众所周知，NK 细胞对于早期治疗至关重要。控制流感感染，令人兴奋的新研究表明 NK 细胞还提供重要的记忆对流感的反应，这一特征以前被认为是 T 细胞和 B 细胞所保留的，我们的数据表明，低剂量的合成食品添加剂叔丁基氢醌 (tBHQ) 会损害 NK 细胞效应功能，具体来说，我们最近发表的研究表明，会对流感的先天免疫反应产生不利影响。体外用 tBHQ 处理活化的 NK 细胞会导致干扰素 γ 的诱导减少 (IFNγ)、穿孔素和颗粒酶——所有这些都是控制体内病毒感染传播的关键分子。此外，我们的研究表明，低剂量 tBHQ 饮食的小鼠 NK 细胞反应受损。肺部 IFNγ+ NK 细胞百分比下降、IFNγ 基因减少证明了流感 IFNγ 和颗粒酶 B 的表达和诱导减弱。这些效应先于 T 细胞受损对流感的反应、病毒负荷增加和支气管肺炎恶化，这与最近的研究表明，NK 细胞反应对于流感中 T 细胞的最佳活性至关重要。先前确定 tBHQ 是免疫细胞中 Nrf2 的有效且强大的激活剂，这表明这些初步数据是我们中央研究的基础。假设，即 tBHQ 通过 Nrf2 依赖性减弱 NK 细胞效应功能和记忆我们建议通过两个具体目标来检验这一假设，目的是确定该机制。其中 tBHQ 抑制 NK 细胞激活和效应功能。这些研究将在野生型和 Nrf2 缺陷模型以确定 Nrf2 在这些效应中的作用我们还将进行单细胞 RNA 分析。测序以确定 tBHQ 对功能不同的 NK 细胞亚群的影响目标 2 是表征 tBHQ 对 NK 细胞记忆发育的影响该目标将利用流式细胞术来识别记忆。 NK 细胞和条件敲除小鼠以确定 Nrf2 对这些细胞功能的作用。