Enhanced infectivity of SARS-CoV-2 in Particulate Matter exposed Sinonasal Epithelial Cells

项目主任/主要研究者（最后，第一，中间）：Ramanathan，Murugappan Jr 据估计，虽然大多数SARS-CoV-2感染者在持续的冠状病毒疾病-2019年 （COVID-19）大流行无症状或症状轻微，住院和死亡率很大程度上 发生在患有合并症的患者中，如肥胖症、糖尿病和COPD。我们理解 环境暴露在改变对SARS-CoV-2的反应中的作用正在显现， 污染，吸烟和电子烟与SARS-CoV-2患者的最差结果有关。那里 是一个时间敏感的迫切需要了解宿主防御机制的鼻窦上皮细胞， 由于环境暴露而受损，可能会增加对SARS-CoV-2的易感性 感染这份行政补充文件将与SARS-CoV-2研究专家合作， 扩大我们在这一关键领域的视野。我们将测试针对宿主防御途径的假设 这一点在空气污染中受到损害，可能会保护和改变对SARS-COV-2的反应 呼吸道感染通过母公司R01赠款，我们已经证明，长期暴露于PM2.5 在表观遗传重编程中起着至关重要的作用我们的研究已经证实转录因子 核因子红细胞样因子2（Nrf2）是抗氧化、抗炎和先天性免疫缺陷的关键激活剂。 免疫防御我们和其他人已经在人类生物标本和动物模型中证明， 长期暴露于PM2.5会导致Nrf2活性下降，这与先天性免疫缺陷有关。 免疫防御在缺乏Nrf2（Nrf2-/-）的小鼠中，病毒和细菌感染引起氧化应激， 与野生型小鼠相比，恶化的肺部炎症、急性肺损伤和更高的死亡率。遗传或 Nrf2途径的药理学活化可以挽救这些作用。Nrf2通路的破坏已经被 显示引起血管紧张素转换酶2（ACE2）的上调， SARS-CoV2进入气道上皮细胞的关键。此外，ACE2基因的低甲基化使 在免疫功能低下的患者中增加ACE2的表达。我们的目标是 行政补充（响应NOT-AI-020 - 031）是为了调查空气串扰 污染暴露、宿主防御和SARS-CoV-2感染。如果这个试点项目成功， Nrf2激活剂的临床前试验将为进一步开发一种新的 防治SARS-CoV-2感染的药物靶点。该提案将利用 我们的团队在空气污染、呼吸道疾病方面的专业知识，以及正在进行BSL-3的病毒学家专家 SARS-CoV-2研究。本项目的成功完成将为未来的研究提供概念证明 旨在开发靶向宿主防御的新策略，用于预防和治疗 SARS-CoV-2感染易感人群。

Program Director/Principal Investigator (Last, First, Middle): Ramanathan, Murugappan Jr It is estimated that while the majority of SARS-CoV-2 infections in the ongoing coronavirus disease-2019 (COVID-19) pandemic are asymptomatic or have mild symptoms, hospitalizations and mortality largely occurs in patients with co-morbid conditions such as obesity, diabetes and COPD. Our understanding of the role of environmental exposures in modifying the response to SARS-CoV-2 is emerging and air pollution, smoking and vaping have been associated with worst outcomes of SARS-CoV-2 patients. There is a time sensitive urgent need to understand host defense mechanisms in the sinonasal epithelia which are compromised due to environmental exposures and may increase susceptibility to SARS-CoV-2 infection. This administrative supplement will forge collaboration with an expert in SARS-CoV-2 research to expand our horizon in this critical area. We will test the hypothesis of targeting a host defense pathway which is compromised in air pollution that may protect and modify the response to SARS-COV-2 respiratory infection. Through the parent R01 grant, we have demonstrated that chronic exposure to PM2.5 has an overarching role in epigenetic reprogramming. Our studies have established that transcription factor Nuclear factor erythroid-factor 2 (Nrf2) is a key activator of anti-oxidative, anti-inflammatory, and innate immune defenses. We and others have demonstrated in human biospecimens and animal models that chronic exposure to PM2.5 causes a decline in Nrf2 activity that correlates with compromised innate immune defenses. In mice deficient for Nrf2 (Nrf2-/-), viral and bacterial infection causes oxidative stress, worsened lung inflammation, acute lung injury and greater mortality compared to wildtype mice. Genetic or pharmacological activation of Nrf2 pathway can rescue these effects. Disruption of Nrf2 pathway has been shown to cause upregulation of angiotensin-converting enzyme 2 (ACE2) which is the functional receptor for SARS-CoV2 entry into airway epithelial cells. Furthermore, hypomethylation of the ACE2 gene has been demonstrated to increase ACE2 expression in immunocompromised patients. The goal for this administrative supplement (in response to NOT-AI-020-031) is to investigate the crosstalk of air pollution exposure, host defense and SARS-CoV-2 infection. If this pilot project is successful, preclinical testing of Nrf2 activators will provide proof of concept for further development a novel drug target for prevention and treatment of SARS-CoV-2 infection. The proposal will leverage expertise of our team on air pollution, respiratory diseases and an expert virologist with ongoing BSL-3 SARS-CoV-2 research. Successful completion of this project will provide proof of concept for future studies directed towards development of a novel strategy of targeting host defense for prevention and treatment of SARS-CoV-2 infection in susceptible populations.