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

项目摘要 这一紧急的竞争性修订将支持快速反应的努力，以确定是否香烟 吸烟引起的气道上皮细胞变化使其更容易感染SARS-CoV-2 吸食大麻（不含尼古丁）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 (i.e.,尼古丁（不吸烟），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， ACE 2，对肺泡上皮细胞的特定亚群。这一知识导致了对 吸烟可能会增加COVID-19传播和进展的风险。有 没有关于吸食大麻或vaping的具体数据，因此临床决策和公众 教育仅限于一般性的警告，即电子烟和吸烟对肺部有害。 免疫力父母R21涉及暴露大鼠从大麻烟雾。研究团队 也有能力将大鼠暴露于电子烟的气溶胶中，包括JUUL， IQOS和万宝路香烟的烟雾。这一紧迫的竞争性修订将允许 额外的实验，以确定（1）如果使用大麻，JUUL，或IQOS可以导致相同的 ACE 2基因表达增加，如吸烟烟草;（2）如果这种上调是导致 尼古丁或吸烟或两者兼而有之;（3）如果这些暴露同样上调病毒的表达， 主要活化蛋白酶TMPRSS 2或替代活化蛋白酶组织蛋白酶B或L;（4） 如果上调发生在眼上皮、血管内皮和心肌;（5）如果 这些基因的上调也是由二手接触引起的;（6）如果停止使用可能 减少表达。这些发现将有助于防止或减轻社区传播 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- 流暴露于大麻烟雾，JUUL电子烟或IQOS的气雾剂，或烟雾 从万宝路或减少尼古丁香烟，影响表达ACE 2，TMPRSS 2，组织蛋白酶 B或组织蛋白酶L。具体目标2是确定二手接触所研究的产品是否 在目标1中，还影响ACE 2、TMPRSS 2、组织蛋白酶B或组织蛋白酶L的表达。这 建议书直接回应了所述的目的和研究目标， NOSI：“NIDA特别感兴趣的是研究收集和审查有关风险的数据， 患有药物使用障碍的个人感染COVID-19的结果. 确定是否使用物质（特别是吸烟或大麻，vaping，阿片类药物） 和其他药物使用）是COVID-19发病和进展的风险因素。

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.”