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.

项目摘要 呼吸道病毒，如流感，每年在美国和全世界杀死数万人， 使其成为全国第八大死亡原因。这种疾病的一个令人困惑的方面是， 个体间反应的变异性。虽然许多人经历了可控的症状，但其他人 患上需要住院治疗的严重疾病。虽然已经确定NK细胞对早期免疫至关重要， 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，以前认为这是T细胞和B细胞的特征。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， 不利地影响对流感的先天免疫应答。具体来说，我们最近发表的研究表明， 在体外用tBHQ处理活化的NK细胞导致干扰素-γ的诱导降低， (IFNγ）、穿孔素和颗粒酶-所有这些都是控制病毒感染在细胞内传播的关键分子。 主持人此外，我们的研究表明，低剂量tBHQ饮食的小鼠具有受损的NK细胞应答 肺中IFNγ+ NK细胞百分比降低，IFNγ基因表达降低， IFNγ和颗粒酶B的表达和减少的诱导。这些效应先于受损的T细胞 对流感的反应，病毒负荷增加和支气管哮喘性肺炎恶化，这与 最近的研究表明，NK细胞应答对于流感中的最佳T细胞活性至关重要。我们有 先前确定tBHQ是免疫细胞中Nrf 2的有效和强大的激活剂，这表明 这些影响的可能机制。这些初步数据是我们的中心的基础。 假设，即tBHQ通过Nrf 2依赖性免疫抑制作用降低NK细胞效应子功能和记忆。 机制我们建议在两个具体目标中检验这一假设。目的1是通过以下方式确定机制： 其中tBHQ抑制NK细胞活化和效应子功能。这些研究将在野生型和 Nrf 2缺陷模型，以确定Nrf 2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对功能上不同的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。这一目标将利用流式细胞术来识别记忆 NK细胞和条件性敲除小鼠，以确定Nrf 2对这些细胞功能的作用。