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

基本信息

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
项目类别：
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

项目摘要

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 年急性综合征呼吸道冠状病毒 2 (SARS-CoV-2)。SARS-CoV-2 是已知的三种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痛苦综合症，这可能是致命的，但是，人们并不同样容易患上严重的综合症。 SARS-CoV-2 感染性疾病 (COVID-19) 的一些风险因素是已知的，包括男性和女性。与代谢性疾病相关的合并症这种流行病是在流行性暴露期间发生的。在美国，每天接触的化学物质称为全氟烷基物质和多氟烷基物质 (PFAS)。 PFAS 污染食品、饮用水、灰尘和空气，导致几乎普遍检测到我们不知道 PFAS 暴露如何影响 SARS-CoV-2 的易感性。感染和 COVID-19 感染气道上皮细胞，引发 Th1 极化亲细胞。感染的消退是由 CD8+ T 细胞介导的感染细胞清除驱动的。游离病毒通过抗体结合而失活，疾病严重程度与淋巴细胞减少有关。 PFAS 是啮齿动物模型中众所周知的免疫抑制剂，可减少 CD4+ T 细胞产生的 IFN-γ。 PFAS 与人类接种疫苗后抗体滴度降低有关。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) 以及它们各自的有趣的是，在体内暴露后，至少 PPARα 被激活。 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。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。假设 PFAS 暴露通过与细胞核相互作用而增强对 SARS-CoV-2 感染的易感性首先，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。 1 我们将生成新型 hACE2/hPPARα 转基因小鼠并检查 SARS-CoV-2 的影响第二，高效 CD4+ T 细胞。 PFAS 功能对于最大限度地降低罹患 COVID-19 的风险至关重要。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，这些结果将提供重要的信息。有关同时接触环境化学品如何增加严重 COVID-19 风险的信息。