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

• 批准号: 10525961
• 负责人: Elizabeth M. Gardner
• 金额: $ 18.8万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10525961
• 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; 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; base; cell type; conditional knockout; cytokine; cytotoxicity; experience; exposed human population; food consumption; immune function; immunotoxicity; in vivo; influenza infection; insight; mortality; novel; pandemic disease; pathogen; perforin; respiratory virus; response; single-cell RNA sequencing; symptom management; transcription factor

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.

项目总结 流感等呼吸道病毒每年在美国和世界各地导致数万人死亡， 使其成为全国第八大死因。这种疾病令人困惑的一个方面是 个体间反应的可变性。虽然许多人的症状是可控的，但其他人 患上需要住院治疗的重病。虽然众所周知，NK细胞在早期阶段非常关键 控制流感感染，令人兴奋的新研究表明，NK细胞也提供了重要的记忆 对流感的反应，这是以前被认为是T细胞和B细胞保留的特征。我们的数据表明 低剂量的合成食品添加剂叔丁基对苯二酚(TBHQ)会损害NK细胞效应功能，并 对流感的先天免疫反应产生不利影响。具体来说，我们最近发表的研究表明 体外用TBHQ处理活化的NK细胞可降低干扰素-γ的诱生 干扰素γ、穿孔素和颗粒酶-所有这些都是控制病毒感染在体内传播的关键分子 主持人。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。 对流感以肺内干扰素γ+NK细胞百分率下降为证，干扰素γ基因下调 干扰素γ和颗粒酶B的表达和诱导减弱这些效应先于受损的T细胞 对流感的反应，增加的病毒负担和恶化的支气管炎，这与 最近的研究表明，在流感中，NK细胞的反应是获得最佳T细胞活性的关键。我们有 先前已经证实，TBHQ是免疫细胞中Nrf2的有效和强大的激活剂，这表明 这些效应的可能机制。这些初步数据是我们中央 假说，即TBHQ通过依赖Nrf2降低NK细胞效应器的功能和记忆 机制。我们建议在两个具体目标上检验这一假设。目标1是通过以下方式确定机制 其抑制NK细胞活化和效应功能。这些研究将在野生型和 Nrf2缺乏的模型来确定Nrf2在这些效应中的作用。我们还将进行单细胞RNA- 测序以确定TBHQ对功能不同的NK细胞亚群的影响。目标2是描述 TBHQ对自然杀伤细胞记忆发育的影响这个目标将利用流式细胞术来识别记忆 NK细胞和条件性基因敲除小鼠，以确定Nrf2对这些细胞功能的作用。