Defining the Impact of Per/Polyfluoroalkyl Substance Exposure on Susceptibility to SARS-CoV-2 Infection and Disease

确定全氟烷基/多氟烷基物质暴露对 SARS-CoV-2 感染和疾病易感性的影响

• 批准号: 10193236
• 负责人: Florian Douam
• 金额: $ 24.3万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193236
• 关键词: 2019-nCoV; ACE2; Acids; Address; Adult Respiratory Distress Syndrome; Agonist; Air; American; Antibodies; Antibody titer measurement; Apoptosis; Binding; Biological; Body Burden; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 severity; Cardiovascular Diseases; Cell physiology; Cells; Chemicals; Coronavirus; Data; Dependovirus; Detection; Development; Diabetes Mellitus; Diet; Disease; Dust; Environment; Epithelial Cells; Evolution; Exposure to; Fire - disasters; Food; Food Contamination; Generations; Genetic Transcription; Human; Hypertension; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Infection; Inflammatory; Inflammatory Response; Interferon Type II; K-18 conjugate; Lower respiratory tract structure; Lymphopenia; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Modeling; Modernization; Mus; Nuclear Receptors; PPAR alpha; Paint; Patients; Pneumonia; Polishes; Predisposition; Production; Prognosis; Propionic Acids; Proteins; Resolution; Resources; Risk; Risk Factors; Rodent Model; Role; SARS-CoV-2 infection; Severity of illness; Stains; T-Lymphocyte; Testing; Textiles; Transgenic Mice; United States; Vaccination; Virus; Water; Waxes; Work; airway epithelium; alveolar epithelium; comorbidity; constitutive androstane receptor; consumer product; coronavirus disease; cost; cytokine; cytokine release syndrome; drinking water; environmental chemical; experience; fighting; humanized mouse; immune function; in vivo; macrophage; male; mouse model; novel; pandemic disease; perfluorooctanoic acid; pregnane X receptor; programs; receptor; risk minimization; severe COVID-19; sex; small hairpin RNA

Project Summary We are in the midst of an unprecedented, modern pandemic as a result of the evolution of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. SARS-CoV-2 is one of three known coronaviruses that can replicate in the lower respiratory tract and cause pneumonia and acute respiratory distress syndrome, which can be fatal. However, people are not equally susceptible to development of severe SARS-CoV-2 infection disease (COVID-19). Some risk factors are known, including male sex and comorbidities related to metabolic disease. This pandemic has occurred during an endemic exposure to a class of chemicals called per- and polyfluoroalkyl substances (PFAS) in the United States. Daily exposures occur via PFAS contaminated food, drinking water, dust and air, resulting in nearly universal detection in people examined. What we do not know is how PFAS exposure may influence susceptibility to SARS-CoV-2 infection and COVID-19. SARS-CoV-2 infects airway epithelial cells, triggering a Th1-polarizing pro- inflammatory response. Resolution of the infection is driven by CD8+ T cell-mediated clearance of infected cells and inactivation of the free virus by antibody-binding. Disease severity is associated with lymphopenia and reduced IFN-γ production by CD4+ T cells. PFAS are well-known immunosuppressive agents in rodent models, and PFAS are associated with reduced antibody titers following vaccinations in humans. Our data, and others, show that PFAS are agonists for nuclear receptors, including peroxisome proliferator activated receptor α (PPARα), constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that their respective transcriptional programs are upregulated following in vivo exposure. Intriguingly, activation of at least PPARα and PXR in T cells results in Th2-skewing, reduced IFN-γ production, and lymphopenia. Here, we propose to examine the interaction between exposure to legacy (perfluorooctanoic acid, PFOA) and replacement (perfluoro(2-methyl-3-oxahexanoic) acid, GenX) PFAS and infection with SARS-CoV-2. We will test the hypothesis that PFAS exposure enhances susceptibility to SARS-CoV-2 infection via interaction with nuclear receptors. First, there are critical, species-specific differences in proteins regulating susceptibility to SARS- CoV-2 infection (angiotensin-converting enzyme 2 (ACE2)) and the biological effects of PFAS (PPARα). In Aim 1 we will generate a novel hACE2/hPPARα transgenic mouse and examine the effects of SARS-CoV-2 infection in mice with human relevant steady-state body burdens of PFAS. Second, efficient CD4+ T cell function is essential for minimizing risk of developing COVID-19. PFAS activate multiple nuclear receptors known to regulate immune function and T cell function. In Aim 2, we will use adeno-associated virus-mediated transduction of PPARα, CAR and PXR shRNA in vivo, to test the necessity for each receptor in enhancing susceptibility to SARS-CoV-2 and how PFOA’s effects are modified. The results will provide essential information on how concurrent exposures to environmental chemicals enhance the risk of severe COVID-19.

项目概要 由于新型严重流行病的演变，我们正处于一场前所未有的现代大流行之中。 2019 年急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。SARS-CoV-2 是已知的三种冠状病毒之一 冠状病毒可以在下呼吸道复制并引起肺炎和急性呼吸道疾病 遇险综合症，这可能是致命的。然而，人们并不同样容易患上严重的疾病 SARS-CoV-2 感染性疾病 (COVID-19)。一些已知的风险因素，包括男性和 与代谢性疾病相关的合并症。这次大流行是在流行性暴露期间发生的 在美国，有一类称为全氟烷基物质和多氟烷基物质 (PFAS) 的化学品。每日曝光量 PFAS 污染食品、饮用水、灰尘和空气，导致几乎普遍检测到 人们检查了。我们不知道的是，PFAS 暴露如何影响 SARS-CoV-2 的易感性 感染和 COVID-19。 SARS-CoV-2 感染气道上皮细胞，触发 Th1 极化亲 炎症反应。感染的消退是由 CD8+ T 细胞介导的感染细胞清除驱动的 以及通过抗体结合使游离病毒失活。疾病严重程度与淋巴细胞减少有关 减少 CD4+ T 细胞产生的 IFN-γ。 PFAS 是啮齿动物模型中众所周知的免疫抑制剂， PFAS 与人类接种疫苗后抗体滴度降低有关。我们的数据和其他人， 表明 PFAS 是核受体的激动剂，包括过氧化物酶体增殖物激活受体 α (PPARα)、组成型雄甾烷受体 (CAR) 和孕烷 X 受体 (PXR) 以及它们各自的 体内暴露后转录程序上调。有趣的是，至少激活了 PPARα T 细胞中的 PXR 会导致 Th2 倾斜、IFN-γ 产生减少和淋巴细胞减少。在此，我们建议 检查遗留（全氟辛酸，PFOA）暴露与替代品之间的相互作用 （全氟（2-甲基-3-氧己酸）酸，GenX）PFAS 与 SARS-CoV-2 感染。我们将测试 假设接触 PFAS 通过与细胞核相互作用而增强对 SARS-CoV-2 感染的易感性 受体。首先，调节 SARS 易感性的蛋白质存在关键的、物种特异性的差异。 CoV-2 感染（血管紧张素转换酶 2 (ACE2)）和 PFAS (PPARα) 的生物学效应。瞄准 1 我们将生成新型 hACE2/hPPARα 转基因小鼠并检查 SARS-CoV-2 的影响 具有人类相关稳态体内 PFAS 负荷的小鼠感染。二、高效CD4+T细胞 功能对于最大限度地降低罹患 COVID-19 的风险至关重要。 PFAS 激活多种核受体 已知可调节免疫功能和 T 细胞功能。在目标 2 中，我们将使用腺相关病毒介导的 体内转导 PPARα、CAR 和 PXR shRNA，以测试每种受体增强的必要性 对 SARS-CoV-2 的易感性以及 PFOA 的作用如何改变。结果将提供必要的 有关同时接触环境化学品如何增加严重 COVID-19 风险的信息。