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: 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
• 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

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，例如影响力，每年在美国和世界范围内杀死成千上万的人 使其成为全国死亡的第八个主要原因。这种疾病的困惑方面之一是 个体反应的变异性。尽管许多人都经历了可管理的符号，而其他人则 患有严重疾病需要住院。虽然可以很好地确定NK细胞对早期至关重要 控制影响力感染的控制，令人兴奋的新研究表明，NK细胞也提供了重要的记忆 对影响力的响应，这是先前被认为是针对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，TERT叔丁基氢醌（TBHQ）会损害NK细胞效应子功能和 不利影响对影响力的先天免疫响应。特别是我们最近发表的研究显示 用TBHQ在体外对活化的NK细胞进行处理导致干扰素伽马诱导降低 （IFNγ），穿孔蛋白和颗粒酶 - 所有这些都是控制病毒感染传播的关键分子 主人。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 影响Za的IFNγ+ NK细胞百分比降低，肺中IFNγ基因的降低证明了 IFNγ和颗粒酶B的表达和诱导降低。这些作用在T细胞受损之前 对影响力的反应，病毒烧伤增加并恶化支气管肺炎，这与 最近的研究表明，NK细胞反应对于影响力的最佳T细胞活性至关重要。我们有 以前确定TBHQ是免疫细胞中NRF2的潜在且可靠的激活剂，该激活剂指向A 这些影响的可能机制。这些初步数据是我们中央的基础 假设，即TBHQ通过NRF2依赖性降低NK细胞效应子功能和内存 机制。我们建议以两个具体目标检验这一假设。目标1是确定机制 TBHQ抑制NK细胞激活和效应子功能。这些研究将以野生型和 NRF2缺乏模型确定NRF2在这些效果中的作用。我们还将执行单细胞RNA- 测序以确定TBHQ对功能差的NK细胞子集的影响。目标2是表征 TBHQ对NK细胞存储器发展的影响。这个目标将利用流式细胞仪来识别内存 NK细胞和条件敲除小鼠确定NRF2对这些细胞功能的作用。