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: 10362610
• 负责人: Florian Douam
• 金额: $ 20.17万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362610
• 关键词: 2019-nCoV; ACE2; Acids; Acute Respiratory Distress Syndrome; Address; 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; Persons; Pneumonia; Polishes; Poly-fluoroalkyl substances; 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.

项目摘要 由于小说的演变，我们正处于前所未有的现代大流行中 2019年急性呼吸综合征冠状病毒2（SARS-COV-2）。SARS-COV-2是已知的三个 可以在下呼吸道复制并引起肺炎和急性呼吸的冠状病毒 遇险综合征，可能是致命的。但是，人们并不容易受到严重发展 SARS-COV-2感染疾病（Covid-19）。已知一些危险因素，包括男性和 合并症与代谢疾病有关。这种大流行是在接触到A的情况下发生的 在美国，称为每类和多氟烷基物质（PFA）的化学物质类别。每日暴露 通过PFA污染的食物，饮用水，灰尘和空气发生，导致几乎普遍的检测 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 感染和共同-19。 SARS-COV-2感染气道上皮细胞，触发Th1违法性 炎症反应。感染的分辨率是由CD8+ T细胞介导的感染细胞驱动的 并通过抗体结合使游离病毒失活。疾病的严重程度与淋巴细胞减少症和 CD4+ T细胞的IFN-γ降低。 PFA是啮齿动物模型中著名的免疫抑制剂， PFA与人类接种后的抗体滴度减少有关。我们的数据以及其他 表明PFA是核接收器的激动剂，包括过氧化物体增殖物激活受体α （PPARα），组成型雄激素受体（CAR）和孕妇X受体（PXR），其相对 在体内暴露后，转录程序上调。有趣的是，至少PPARα的激活 T细胞中的PXR和PXR导致Th2稳定，减少IFN-γ的产生和淋巴细胞减少。在这里，我们建议 检查暴露于遗产（Pertluorooctanoic，PFOA）和更换之间的相互作用 （全氟（2-甲基-3-氧气）酸，genx）PFA和SARS-COV-2感染。我们将测试 假设PFAS暴露通过与核相互作用增强对SARS-COV-2感染的敏感性 受体。首先，在调节SARS- COV-2感染（血管紧张素转化酶2（ACE2））和PFAS（PPARα）的生物学作用。目标 1我们将生成一种新型的HACE2/HPPARα转基因小鼠并检查SARS-COV-2的影响 PFA的人类相关稳态燃烧的小鼠感染。第二，有效的CD4+ T细胞 功能对于最大程度地减少开发Covid-19的风险至关重要。 PFA激活多个核接收器 已知可以调节免疫功能和T细胞功能。在AIM 2中，我们将使用与腺相关的病毒介导的 PPARα，CAR和PXR SHRNA在体内的转导，以测试每个受体的必要条件以增强 对SARS-COV-2的敏感性以及PFOA的效果如何被修改。结果将提供必不可少的 有关以及对环境化学物质的同时暴露如何增强严重共同Covid-19的风险的信息。