Upregulation of SARS-CoV-2 receptor and activation proteases by marijuana smoke and e-cigarette aerosols

项目概要 这项紧急的竞争性修订将支持快速反应工作，以确定卷烟是否 吸烟引起的气道上皮变化使其更容易感染 SARS-CoV-2 吸食大麻（不含尼古丁的烟雾）或使用电子产品也会导致感染 尼古丁输送系统 (ENDS)，包括电子烟和加热烟草产品 IQOS （即不含烟雾的尼古丁），包括二手接触。烟草烟雾被认为 通过增加 SARS-CoV-2 受体的表达来增加对 COVID-19 的易感性， ACE2，作用于肺泡上皮细胞的特定亚群。这些知识为我们提供了建议 公众认为吸烟可能会增加 COVID-19 传播和进展的风险。有 不是有关吸食大麻或电子烟的具体数据，因此临床决策和公众 教育仅限于一般警告，即电子烟和吸烟对肺部有害 免疫力。母体 R21 涉及让老鼠接触大麻烟雾。研究团队 还能够将大鼠暴露于电子烟的气溶胶中，包括 JUUL、来自电子烟的气溶胶 IQOS，以及万宝路红香烟的烟雾。这项紧急的竞争性修订将允许 额外的实验以确定 (1) 使用大麻、JUUL 或 IQOS 是否会导致相同的结果 与吸烟一样，ACE2 基因表达增加； (2) 如果这种上调是结果 尼古丁或烟雾或两者兼而有之； (3) 如果这些暴露同样上调病毒的表达’ 主要激活蛋白酶TMPRSS2或替代激活蛋白酶组织蛋白酶B或L； (4) 如果眼上皮、血管内皮和心肌发生上调； (5) 如果 这些基因的上调也是由二手暴露引起的； (6) 如果停止可能 然后减少表达。这些发现将有助于预防或减轻社区传播 COVID-19，特别是在物质使用人群中。具体目标 1 是确定是否主要 接触大麻烟雾、JUUL 电子烟或 IQOS 气溶胶或烟雾 来自万宝路或低尼古丁香烟，影响 ACE2、TMPRSS2、组织蛋白酶的表达 B 或组织蛋白酶 L。具体目标 2 是确定是否二手接触所研究的产品 目标 1 中的内容还影响 ACE2、TMPRSS2、组织蛋白酶 B 或组织蛋白酶 L 的表达。 提案直接响应该项目的既定目的和研究目标 NOSI：“NIDA 对收集和检查有关风险和风险的数据的研究特别感兴趣。 患有物质使用障碍的个体感染 COVID-19 的结果…… 确定是否使用药物（特别是吸烟草或大麻、电子烟、阿片类药物） 和其他药物使用）是 COVID-19 发病和进展的危险因素。”

PROJECT SUMMARY This urgent competitive revision will support a rapid response effort to determine if cigarette smoking-induced changes in airway epithelium that make it more susceptible to SARS-CoV-2 infection also result from marijuana smoking (smoke without nicotine), or from use of electronic nicotine delivery systems (ENDS) including e-cigarettes and the heated tobacco product IQOS (i.e., nicotine without smoke), including secondhand exposure. Tobacco smoke is thought to increase susceptibility to COVID-19 by increasing expression of the SARS-CoV-2 receptor, ACE2, on specific subsets of alveolar epithelial cells. This knowledge has led to advice to the public that smoking may increase the risk of COVID-19 transmission and progression. There are not specific data about smoking cannabis or vaping, so clinical decision making and public education is limited to a general admonition that vaping and smoking are harmful to pulmonary immunity. The parent R21 involves exposing rats to smoke from marijuana. The research team also has the capability to expose rats to aerosol from e-cigarettes including JUUL, aerosol from IQOS, and smoke from Marlboro Red cigarettes. This urgent competitive revision will permit additional experiments to determine (1) if use of marijuana, JUUL, or IQOS can cause the same increase in ACE2 gene expression as does smoking tobacco; (2) if this upregulation is a result of nicotine or smoke or both; (3) if these exposures similarly upregulate expression of the virus’ main activation protease TMPRSS2 or the alternative activation proteases cathepsin B or L; (4) if upregulation occurs in ocular epithelium, vascular endothelium, and myocardium; (5) if the upregulation of these genes is also caused by secondhand exposure; and (6) if cessation might then reduce expression. These findings will help to prevent or mitigate community spread of COVID-19, especially in substance-using populations. Specific Aim 1 is to determine if main- stream exposure to smoke from marijuana, aerosol from JUUL e-cigarettes or IQOS, or smoke from Marlboro or reduced-nicotine cigarettes, affects expression of ACE2, TMPRSS2, cathepsin B, or cathepsin L. Specific Aim 2 is to determine if secondhand exposure to the products studied in Aim 1 also affects expression of ACE2, TMPRSS2, cathepsin B, or cathepsin L. This proposal is directly responsive to the stated purpose and research objectives of the NOSI: “NIDA is especially interested in research collecting and examining data on the risks and outcomes for COVID-19 infection in individuals suffering from substance use disorders… determine whether substance use (especially smoking tobacco or marijuana, vaping, opioids and other drug use) is a risk factor for the onset and progression of COVID-19.”