Lung Innate COVID-19 Defense Specific to Veterans Risk Characteristics

针对退伍军人风险特征的肺部先天性 COVID-19 防御

• 批准号: 10151991
• 负责人: Kristina L Bailey
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10151991
• 关键词: 2019-nCoV; ACE2; Address; Affect; Age; Aging; Alcohol abuse; Alcohols; Alveolar Macrophages; Binding; COVID-19; COVID-19 mortality; COVID-19 pandemic; Cells; Cessation of life; Characteristics; Chronic Obstructive Airway Disease; Chronic lung disease; Cilia; Clinical; Collectins; Communities; Contracts; Coronavirus; Coronavirus Infections; Coronavirus spike protein; Country; Data; Defense Mechanisms; Defensins; Disease; Elderly; Enzymes; Epidemiology; Epithelial Cells; Functional disorder; Future; GRP78 gene; General Population; Health; Human; Immune; Impairment; Individual; Infection; Innate Immune System; Knowledge; Lead; Lung; Lung diseases; Medical; Modality; Mucociliary Clearance; Mucous body substance; Natural Immunity; Outcome; Patients; Physicians; Population; Predisposing Factor; Predisposition; Preventive care; Process; Proteins; Pulmonary Surfactant-Associated Protein D; Research; Research Personnel; Research Support; Risk; Risk Factors; Role; Route; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Scientist; Site; Smoking; Structure; Symptoms; Testing; Time; Tissues; Veterans; Viral; Virus; Virus Diseases; Virus Receptors; Vulnerable Populations; Work; Writing; age effect; airway epithelium; alcohol misuse; alcohol use disorder; antimicrobial; base; biobank; career; cigarette smoking; experience; high risk; high risk population; human old age (65+); infection rate; injury and repair; lung injury; macrophage; military veteran; mortality; novel coronavirus; pandemic disease; particle; prevent; pulmonary function; receptor; receptor function; response; skills; surfactant

COVID-19 is now a global pandemic requiring a rapid and concerted response from the scientific and medical community. Based upon recent epidemiology derived only months earlier from the earliest affected countries, the pathogenesis of the SARS-CoV-2 virus and clinical outcomes from COVID-19 are far worse in individuals with certain pre-existing conditions and those of advanced age. It is essential to the health of Veterans to fully define which at-risk conditions particularly impact them and their unique needs and to do so immediately in order to empower clinical preventive care during this and future viral pandemics. Compared to the general public, the Veterans population can be characterized by older age, cigarette smoking leading to pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD), and alcohol use disorders (AUD). Our knowledge about how such characteristics impact SARS-CoV-2 pathogenesis is limited. However, results from our previous VA-supported research have already demonstrated that old age and AUD are associated with cilia dysfunction. Our results also demonstrate that AUD results in decreased surfactant anti-microbial action. Surfactant protein D has been documented to specifically bind to and neutralize the Spike protein of coronavirus. We hypothesize that altered innate lung defense at the level of mucociliary clearance, anti- microbial surfactants, and viral receptor function will negatively impact susceptibility and pathogenesis of SARS-CoV-2, placing Veterans particularly in harm’s way. Our assembled team of investigators include a VA Research Career Scientist with 25 years’ experience in the impact of alcohol on lung injury and repair, a physician-scientist at the VA whose expertise is on the impact of age in lung function, and a microbiologist who is already experienced in working with SARS-CoV-2 under BSL3 conditions. Combined with our existing biobank of human lung cells and tissues, we propose to address our hypothesis by identifying any differences in SARS-CoV-2 infection responses between normal airway epithelium and lung macrophages and those cells collected from individuals with COPD, with AUD, or of old age. We will specifically identify in these groups any changes in cilia beat controlling clearance, surfactant protein D expression/structure/function, and known SARS-CoV-2 receptors. Such studies will be performed for the first time in these high-risk groups common to the VA population. Defining the modalities of risk will empower clinicians to make informed clinical preventive care decisions for Veterans.

新冠肺炎现在是一场全球性的流行病，需要科学和医学界迅速做出协调一致的反应 社区。根据几个月前从最早受影响国家得出的最新流行病学， SARS-CoV-2病毒的致病机制和新冠肺炎的临床结果对个人来说要糟糕得多 有某些预先存在的疾病和那些高龄的。对退伍军人的健康至关重要的是充分 确定哪些风险条件对他们及其独特需求有特别影响，并立即在 以便在这次和未来的病毒大流行期间加强临床预防护理。与一般的 在公众中，退伍军人人口的特点是年龄较大，吸烟导致预先存在 慢性阻塞性肺疾病(COPD)和酒精使用障碍(AUD)等肺部疾病。我们的 关于这些特征如何影响SARS-CoV-2发病机制的知识有限。然而，结果来自 我们之前的退伍军人事务部支持的研究已经证明，老年和AUD与 纤毛功能障碍。我们的结果还表明，AUD会降低表面活性剂的抗微生物作用。 表面活性蛋白D已被证明能特异性地结合和中和 冠状病毒。我们假设，在粘液纤毛清除水平上改变了先天肺防御，抗- 微生物表面活性物质和病毒受体功能将对肺炎易感性和发病机制产生负面影响 SARS-CoV-2，将退伍军人置于特别危险的境地。我们集结的调查团队包括一名退伍军人 研究职业科学家，在酒精对肺损伤和修复的影响方面有25年的经验，a 退伍军人事务部内科医生-科学家，他的专长是年龄对肺功能的影响，以及一位微生物学家 已经有在BSL3条件下处理SARS-CoV-2的经验。结合我们现有的 人类肺细胞和组织的生物库，我们建议通过识别任何差异来解决我们的假设 SARS-CoV-2感染时正常呼吸道上皮和肺巨噬细胞之间的反应 收集自慢性阻塞性肺病、澳门氏症或老年患者。我们将在这些小组中特别确定任何 纤毛节拍控制清除、表面活性蛋白D表达/结构/功能的变化 SARS-CoV-2受体。这样的研究将首次在这些共同的高危人群中进行 退伍军人事务部的人口。明确风险的形式将使临床医生能够在知情的情况下进行临床预防 照顾退伍军人的决定。