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

基本信息

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
项目类别：
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

项目摘要

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，2019年冠状病毒病（Covid-19）已有480万人死亡。 COVID-19是由严重急性呼吸综合症2（SARS-COV-2）引起的一种传染病。 SARS-COV-2感染后的发病率和死亡率主要是由于炎症的强劲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）。 SARS-COV-2感染后，个体表现出不同程度的疾病严重程度。人类表面活性剂蛋白A和D（HSP-A和HSP-D），C型凝集素的两个成员（表面活性剂集合）是图案识别蛋白，它们在一线宿主的防御和先天免疫力中发挥着至关重要的作用肺部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证明了 HSP-A和HSP-D可以与SARS-COV-2尖峰蛋白结合，并抑制肺中的病毒进入和复制上皮细胞。有趣的是，HSP-A和HSP-D的基因是高度多态的，几种遗传变异（等位基因）在普通人群中已经确定了它们中的每一个。但是，HSP-的机械作用 Covid-19的发病机理中的A和HSP-D遗传变异是未知的。长期目标是确定 HSP-A和HSP-D遗传变异的作用在易感性和对SARS-COV-2诱导的ALI/ARDS的严重性并开发新的变异特异性治疗药物来治疗COVID-19。该建议旨在确定表面活性剂收集和尖峰蛋白的分子相互作用，并定义 HSP-A和HSP-D遗传变异，导致COVID-19。我们的中心假设是 HSP-A和HSP-D遗传变异差异影响SARS-COV-2诱导的易感性和严重程度通过抑制SARS-COV-2感染性并调节粘膜先天免疫和病理生理学，ALI/ARDS。最近，我们生成了一个新的双人类转基因（双HTG）鼠标模型，该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模型为我们提供了一种强大的工具，可以研究先天免疫反应和 SARS-COV-2感染后HSP-A和HSP-D变体的机械作用。我们提出了两个具体目标测试我们的假设：目标1：研究HSP-A或HSP-D遗传变异与SARS-COV-2 Spike的相互作用蛋白质和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遗传变异在抑制病毒感染性和通过SARS-COV-2诱导的ALI通过调节双HTG小鼠模型中的TLR/NF-KB/IFN信号传导。该提议得到了我们的强烈支持初步数据和可用的新型双HTG模型，适用于COVID-19研究。我们期望成功完成拟议的研究将建立一个新颖的Covid-19鼠模型，并具有更好的了解HSP-A和HSP-D在Covid-19发病机理中的先天免疫作用，这对开发新颖的免疫调节疗法和个性化医学。