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: 10662530
• 负责人: GUIRONG WANG
• 金额: $ 20.38万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662530
• 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; Cellular biology; Cessation of life; Code; Collagen; Collectins; Collection; Communicable Diseases; Country; Data; Development; Disease; Disease Outcome; 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 Biology; Morbidity - disease rate; Mucous Membrane; Mus; NF-kappa B; Natural Immunity; Nuclear; Organ; Outcome; Pathogenesis; Patients; Pattern Recognition; Persons; Pharmacotherapy; Play; Population; 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; SARS-CoV-2 variant; Severities; Severity of illness; Signal Pathway; Signal Transduction; Surface; System; Techniques; Testing; Therapeutic; Transgenic Mice; Transgenic Model; United States; Variant; Viral; Viral Load result; alveolar epithelium; 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.

不到两年的时间里，已有超过 480 万人死于 2019 年冠状病毒病 (COVID-19)。 COVID-19 是由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）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的大量涌入 细胞和细胞因子进入肺部，导致急性肺损伤（ALI）和急性呼吸窘迫综合征 （ARDS）。感染 SARS-CoV-2 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（表面活性剂集合素）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在 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 可以与 SARS-CoV-2 Spike 蛋白结合并抑制病毒进入肺部和复制 上皮细胞。有趣的是，hSP-A和hSP-D的基因具有高度多态性，并且存在多个遗传变异体 他们每个人的（等位基因）都已在普通人群中被确定。然而，hSP-的机制作用 COVID-19 发病机制中的 A 和 hSP-D 遗传变异尚不清楚。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 并开发用于治疗 COVID-19 的新型变异特异性治疗药物。该提案旨在 确定表面活性剂集合和刺突蛋白的分子相互作用，并定义其机械作用 hSP-A 和 hSP-D 基因变异导致个体对 COVID-19 易感性。我们的中心假设是 hSP-A 和 hSP-D 基因变异对 SARS-CoV-2 诱导的易感性和严重程度有不同影响 通过抑制 SARS-CoV-2 感染性和调节粘膜先天免疫和病理生理学来治疗 ALI/ARDS。 最近，我们构建了一种新的双人源化转基因（double-hTG）小鼠模型，该模型 表达人血管紧张素转换酶-2（SARS-CoV-2同源受体）和 hSP-A 或 hSP-D 遗传 变体。这种双 hTG 模型为我们提供了研究先天免疫反应和 SARS-CoV-2 感染后 hSP-A 和 hSP-D 变体的机制作用。我们提出两个具体目标 检验我们的假设：目标 1：研究 hSP-A 或 hSP-D 遗传变异与 SARS-CoV-2 刺突的相互作用 蛋白及其对肺上皮细胞中病毒进入和复制的抑制作用。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/NF-kB/IFN 信号传导。该提案得到了我们的大力支持 适用于 COVID-19 研究的初步数据和可用的新型双 hTG 模型。我们期望 成功完成拟议的研究将建立一种新型的 COVID-19 小鼠模型，并有更好的效果 了解 hSP-A 和 hSP-D 在 COVID-19 发病机制中的先天免疫作用对于 开发新型免疫调节疗法和个性化医疗。