The UNC Chapel Hill Superfund Research Program (UNC-SRP)

摘要 这项提案是作为北卡罗来纳大学的紧急竞争修订提交的 (UNC)超级基金研究计划(SRP)与2019年冠状病毒病(新冠肺炎) 大流行。我们的重点是无机砷(IAS)，有毒物质登记机构的第一号污染物 (ATSDR)污染了全球的饮用水。IAS对身体的许多器官都有毒性，作为一种 致癌物、糖尿病原、神经毒剂和免疫抑制剂。值得注意的是，在北卡罗来纳州的几个 饮用水中IAS水平高的县，严重急性呼吸综合征的患病率 冠状病毒2(SARS-CoV-2)的感染率也很高，表明有可能同时接触IAS和SARS-CoV-2 发生。这种同时接触IAS对SARS-CoV-2感染易感性和新冠肺炎严重程度的影响 已经研究过了。这项建议的目标是描述IAS暴露和SARS-CoV之间的相互作用。 2人原代鼻腔上皮细胞感染，建立了体外呼吸道感染模型 感染，以及一种新的人源化hAS3MT小鼠品系，其中IAS的代谢和其处置 代谢物类似于人类体内的代谢物。在一种强有力的跨学科方法中，我们将使用差异化 原代人鼻上皮细胞和人源化hAS3MT小鼠来验证慢性鼻炎的假说 暴露于IAS会增加对SARS-CoV2感染的易感性和新冠肺炎的严重程度。而当 结合人类和小鼠的模型，我们还将检查性别和遗传背景在 疾病结局。新增加的两个目标包括：(目标1)确定IAS及其代谢物对以下方面的影响 SARS-CoV-2在分化的原代人鼻上皮细胞中的感染；以及(目标2)表征其影响 免疫球蛋白暴露对非典冠状病毒2型MA感染和新冠肺炎移植小鼠结局的影响。在目标1中，我们测试 假设是暴露在IAS或其代谢产物中会增加SARS-CoV-2的易感性和严重性 人类鼻腔上皮细胞的感染。在目标2中，我们将比较免疫反应、病毒滴度、肺 HAS3MT小鼠暴露于0、40和400 ppb饮用水中的IAS并感染 北卡罗来纳大学教堂山分校最近创造了一种老鼠适应的SARS-CoV-2病毒。评估性的作用 在遗传学方面，我们将使用具有C57BL/6NCr1和129S6/SvEvTac背景的雄性和雌性hAS3MT小鼠。 这项拟议的研究利用了只有北卡罗来纳大学才有的、唯一适合的新型实验室模型。 用于研究环境IAS暴露与SARS-CoV2感染之间的相互作用。建议数 研究解决了理解广泛的环境之间相互作用的迫切需要 暴露和影响全球数亿人的大流行感染。

ABSTRACT This proposal is being submitted as an Emergency Competitive Revision for the University of North Carolina (UNC) Superfund Research Program (SRP) in the context of the Coronavirus Disease 2019 (COVID-19) pandemic. We focus on inorganic arsenic (iAs), the #1 contaminant of the Agency for Toxic Substances Registry (ATSDR) contaminating drinking water around the globe. iAs is toxic to many organs in the body, acting as a carcinogen, diabetogen, neurotoxicant, and immunosuppressant. Notably, in several of the North Carolina counties where iAs levels in drinking water are high, the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is also high, indicating that a co-exposure to iAs and SARS-CoV-2 likely occurs. This co-exposure to iAs on the susceptibility to SARS-CoV-2 infection and COVID-19 severity has never been studied. The goal of this proposal is to characterize the interaction between iAs exposure and SARS-CoV- 2 infection using differentiated primary human nasal epithelial cells, an established in vitro model for respiratory infections, and a novel humanized hAS3MT mouse strain, in which the metabolism of iAs and disposition of its metabolites resemble those in humans. In a strong, transdisciplinary approach, we will use differentiated primary human nasal epithelial cells and a humanized hAS3MT mice to test the hypothesis that chronic exposure to iAs enhances susceptibility to SARS-CoV2 infection and severity of COVID-19. While integrating human and mouse models, we will also examine the role of sex and genetic background on the disease outcome. The two new additional Aims include: (Aim 1) Identify the effects of iAs and its metabolites on SARS-CoV-2 infection in differentiated primary human nasal epithelial cells; and (Aim 2) Characterize the effects of iAs exposure on SARS-CoV-2 MA infection and COVID-19 outcomes in hAS3MT mice. In Aim 1, we test the hypothesis is that exposure to iAs or its metabolites enhances susceptibility to and severity of SARS-CoV-2 infection in the human nasal epithelial cells. In Aim 2, we will compare immune response, viral titer, lung pathology and mortality in hAS3MT mice exposed to iAs in drinking water (0, 40, or 400 ppb) and infected with a mouse-adapted SARS-CoV-2 that has been recently created at UNC Chapel Hill. To assess the role of sex and genetics, we will use male and female hAS3MT mice with C57BL/6NCrl and 129S6/SvEvTac backgrounds. The proposed research utilizes novel laboratory models that are available only at UNC and are uniquely suited for studies of the interaction between environmental iAs exposure and SARS-CoV2 infection. The proposed research addresses a critical need for understanding of the interaction between a widespread environmental exposure and a pandemic infection that affects hundreds of millions of people worldwide.