Impact of chronic ethanol consumption on lung functional and immunological landscape and implication for susceptibility to SARSCoV2 infection

项目摘要 截至本提案提交之日，已有超过3800万例COVID-19病例，其中包括100万例死亡病例。 全世界报道。COVID-19是由新型冠状病毒SARS-CoV-2引起的呼吸道疾病， 范围从轻度到重度/致命性疾病，其特征为过度肺部炎症、急性呼吸道感染、 窘迫综合征（ARDS）、凝血病和多器官衰竭。目前的研究表明， 骨髓细胞亚群在疾病的发展和恶化，但肺居民的确切作用， 巨噬细胞和浸润单核细胞在COVID-19发病机制中的作用仍然知之甚少。已经是 已经确定慢性重度饮酒（CHD）是发展ARDS的重要危险因素， 肺炎患者入住重症监护室（ICU）。CHD也与增加 易受细菌和病毒肺部感染，特别是呼吸道合胞病毒（RSV）， 社区获得性肺炎和肺结核。上皮屏障缺陷以及抗微生物功能 肺泡巨噬细胞的数量被认为是增加呼吸系统疾病易感性的主要原因， CHD患者。尽管冠心病与严重肺动脉高压风险增加之间存在明确的相关性， 由于CHD感染的严重性，迄今为止还没有研究检查CHD对SARS-CoV-2免疫应答的影响。在 在这项应用中，我们提出了一个假设，即慢性饮酒会改变肺内的 骨髓细胞导致对SARS-CoV-2的炎症反应加剧， 间隙为了验证这一假设，我们将利用恒河猴自愿乙醇自我模型， 准确反映人体生理学和概括复杂的人类饮酒行为的管理。 使用这个模型，我们最近证明了CHD导致转录和表观遗传重新布线， 循环单核细胞和脾巨噬细胞，导致异常炎症反应。额外 初步研究表明，随着I型IFN对RSV应答的降低，炎性因子的产生增加 感染以及降低肺泡巨噬细胞的吞噬能力在CHD动物。我们将首先 检查CHD对肺驻留免疫表型、功能和转录景观的影响， 细胞然后，我们将研究CHD对肺部驻留免疫细胞对SARS-CoV-2的反应的影响。 感染这些实验的完成将使我们能够确定CHD介导的肺免疫功能的差异， 对SARS-CoV-2感染的反应，调节COVID 19疾病的进展和严重程度。

PROJECT SUMMARY As of the submission of this proposal, over 38 million cases of COVID-19 including a million deaths have been reported worldwide. COVID-19 is a respiratory disease caused by the novel coronavirus SARS-CoV-2 that can range from a mild to a severe/fatal disease characterized by excessive lung inflammation, acute respiratory distress syndrome (ARDS), coagulopathy, and multi-organ failure. Current studies suggest a major role for myeloid cell subsets in the development and exacerbation of disease, but the precise roles of lung-resident macrophages and infiltrating monocytes in COVID-19 pathogenesis remains poorly understood. It is already well-established that chronic heavy alcohol drinking (CHD) is a significant risk factor for developing ARDS and admission to the intensive care unit (ICU) for patients with pneumonia. CHD is also associated with increased susceptibility to both bacterial and viral pulmonary infections, notably respiratory syncytial virus (RSV), community-acquired pneumonia, and tuberculosis. Defects in epithelial barrier as well as anti-microbial functions of alveolar macrophage are believed to be major causes for increased vulnerability to respiratory diseases in individuals with CHD. Despite the clear association between CHD and increased risk of severe pulmonary infections, no studies to date have examined the impact of CHD on the immune response to SARS-CoV-2. In this application, we propose to test the hypothesis that chronic alcohol drinking alters lung-resident myeloid cells leading to exacerbated inflammatory response to SARS-CoV-2 with reduced viral clearance. To test this hypothesis, we will leverage a rhesus macaque model of voluntary ethanol self- administration that accurately mirrors human physiology and recapitulates complex human drinking behavior. Using this model, we recently demonstrated that CHD results in transcriptional and epigenetic rewiring of circulating monocytes and splenic macrophages, resulting in aberrant inflammatory responses. Additional preliminary studies show enhanced production of inflammatory factors with reduced type I IFN response to RSV infection as well as decreased phagocytic capacity of alveolar macrophages in CHD animals. We will first examine the impact of CHD on the phenotypic, functional and transcriptional landscape of lung-resident immune cells. Then, we will examine the impact of CHD on the response of lung-resident immune cells to SARS-CoV-2 infection. Completion of these experiments will allow us to define CHD-mediated differences in the lung immune response to SARS-CoV-2 infection that modulate COVID19 disease progression and severity.