Roles of human surfactant collectin variants in the susceptibility of COVID-19

人类表面活性剂集合素变体在 COVID-19 易感性中的作用

• 批准号: 10510706
• 负责人: GUIRONG WANG
• 金额: $ 24.45万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510706
• 关键词: 2019-nCoV; ACE2; Acute Lung Injury; Acute Respiratory Distress Syndrome; Alleles; Amino Acids; Antibodies; Binding; C-Type Lectins; COVID-19; COVID-19 pathogenesis; COVID-19 susceptibility; COVID-19 treatment; Cells; Cessation of life; Code; Collagen; Collectins; Collection; Communicable Diseases; Data; Development; Disease; Disease Outcome; Epithelial; Epithelial Cells; Exhibits; Functional disorder; General Population; Genes; Genetic Polymorphism; Genetic Variation; Goals; Host Defense; Human; Immune; In Vitro; Individual; Inflammatory; Innate Immune Response; Interdisciplinary Study; Interferons; Investigation; Link; Lung; Microbe; Modeling; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Mucous Membrane; Mus; NF-kappa B; Natural Immunity; Nuclear; Organ; Outcome; Pathogenesis; Patients; Pattern Recognition; Persons; Pharmacotherapy; Play; Positioning Attribute; Predisposition; Proteins; Public Health; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Reporting; Research; Respiratory Tract Infections; Role; SARS-CoV-2 B.1.617.2; SARS-CoV-2 inhibitor; SARS-CoV-2 pathogenesis; SARS-CoV-2 spike protein; Severities; Severity of illness; Signal Pathway; Signal Transduction; Surface; System; Techniques; Testing; Therapeutic; Transgenic Organisms; United States; Variant; Viral; Viral Load result; alveolar epithelium; base; carbohydrate structure; cytokine; design; disease phenotype; genetic variant; genome wide association study; immunomodulatory therapies; immunoregulation; in vivo; innate immune function; innovation; member; mortality; mouse model; novel; novel therapeutic intervention; personalized medicine; post SARS-CoV-2 infection; receptor; surfactant; tool; viral entry inhibitor; virology

More than 4.8 million people have died due to coronavirus disease 2019 (COVID-19) in less than two years. COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Morbidity and mortality following SARS-CoV-2 infection are predominantly due to a robust influx of inflammatory cells and cytokines into the lungs resulting in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Individuals exhibited different degree of disease severity after SARS-CoV-2 infection. Human Surfactant proteins A and D (hSP-A and hSP-D), two members of C-type lectin (surfactant collectin), are pattern recognition proteins, and they play a critical role as a first-line host defense and innate immunity in the mucosal surfaces of the lung and other organs. Our preliminary data and recent in vitro studies demonstrated that hSP-A and hSP-D can bind to SARS-CoV-2 Spike protein and inhibit viral entry and replication in lung epithelial cells. Interestingly, the genes of hSP-A and hSP-D are highly polymorphic, and several genetic variants (alleles) for each of them have been identified in the general population. However, the mechanistic roles of hSP- A and hSP-D genetic variants in the pathogenesis of COVID-19 are unknow. The long-term goal is to determine the roles of hSP-A and hSP-D genetic variants in susceptibility and severity to SARS-CoV-2-induced ALI/ARDS and to develop novel variant-specific therapeutic drug for the treatment of COVID-19. This proposal aims to determine molecular interaction of surfactant collection and Spike protein, and define the mechanistic roles of hSP-A and hSP-D genetic variants causing individual susceptibilities to COVID-19. Our central hypothesis is that hSP-A and hSP-D genetic variants differentially influence susceptibility and severity to SARS-CoV-2-induced ALI/ARDS by inhibiting SARS-CoV-2 infectivity and modulating mucosal innate immunity and pathophysiology. Recently, we have generated a new double-humanized transgenic (double-hTG) mouse model, which express human angiotensin-converting enzyme-2 (SARS-CoV-2 cognate receptor) and hSP-A or hSP-D genetic variant. This double-hTG model provides us with a powerful tool to study the innate immune response and mechanistic roles of hSP-A and hSP-D variants following SARS-CoV-2 infection. We propose two specific aims to test our hypothesis: Aim 1: Study the interactions of hSP-A or hSP-D genetic variants with SARS-CoV-2 spike protein and the inhibitory effect on viral entry and replication in lung epithelial cells. Aim 2: Define the differential roles of hSP-A genetic variants in inhibiting viral infectivity and modulating SARS-CoV-2-induced ALI through regulating TLRs/NF-kB/IFN signaling in a double-hTG mouse model. The proposal is strongly supported by our preliminary data and available novel double-hTG model suitable for COVID-19 study. We expect that the successful completion of the proposed studies will establish a novel COVID-19 murine model, and have a better understanding of the innate immune roles of hSP-A and hSP-D in COVID-19 pathogenesis that is crucial to develop novel immunomodulatory therapies and personalized medicine.

在不到两年的时间里，已有480多万人死于冠状病毒病2019(新冠肺炎)。 新冠肺炎是由严重急性呼吸综合征冠状病毒2型引起的传染病。 SARS-CoV-2感染后的发病率和死亡率主要是由于炎症性疾病的强劲涌入 细胞和细胞因子进入肺导致急性肺损伤(ALI)和急性呼吸窘迫综合征 (ARDS)。SARS-CoV-2感染后，个体表现出不同程度的疾病严重程度。人类 表面活性蛋白A和D(HSP-A和HSP-D)是C型凝集素的两个成员。 模式识别蛋白，它们作为一线宿主防御和先天免疫发挥关键作用。 肺和其他器官的粘膜表面。我们的初步数据和最近的体外研究表明 HSP-A和HSP-D能与SARS-CoV-2刺突蛋白结合，抑制病毒在肺内的侵入和复制 上皮细胞。有趣的是，HSP-A和HSP-D的基因是高度多态的，并且有几个遗传变异 (等位基因)在普通人群中已被确定。然而，热休克蛋白的机械性作用-- A和HSP-D基因变异在新冠肺炎发病机制中的作用尚不清楚。长期目标是确定 HSP-A和HSP-D基因变异在SARS-CoV-2诱导的ALI/ARDS易感性和严重程度中的作用 并开发治疗新冠肺炎的新型变种特异性治疗药物。这项建议旨在 确定表面活性物质收集和Spike蛋白的分子相互作用，并确定其机制作用 热休克蛋白-A和热休克蛋白-D基因变异导致个体对新冠肺炎易感。我们的中心假设是 HSP-A和HSP-D基因变异对SARS-CoV-2易感性和严重程度的不同影响 通过抑制SARS-CoV-2的感染性，调节粘膜天然免疫和病理生理，达到ALI/ARDS的目的。 最近，我们建立了一种新的双人化转基因(Double-HTG)小鼠模型，该模型 人血管紧张素转换酶-2(SARS-CoV-2同源受体)与HSP-A或HSP-D基因的表达 变种。这种双HTG模型为我们研究先天免疫反应和 SARS-CoV-2感染后HSP-A和HSP-D变异的机制作用我们提出了两个具体目标 为了验证我们的假设：目的1：研究HSP-A或HSP-D基因变异与SARS-CoV-2尖峰的相互作用 蛋白和抑制病毒进入和复制肺上皮细胞的作用。目标2：定义差异 HSP-A基因变异在抑制病毒感染性和调节SARS-CoV-2诱导的ALI中的作用 在双HTG小鼠模型中调节TLRs/核因子-kB/干扰素信号。这项建议得到了我们的大力支持 初步数据和适用于新冠肺炎研究的新型双HTG模型。我们预计， 建议研究的成功完成将建立一种新颖的新冠肺炎小鼠模型，并具有更好的 了解热休克蛋白-A和热休克蛋白D在新冠肺炎发病机制中的先天免疫作用 开发新的免疫调节疗法和个性化药物。