Mechanisms of lung and cardiac pathology in SARS-CoV-2 infections

SARS-CoV-2 感染中的肺和心脏病病理机制

• 批准号: 10649990
• 负责人: Amal O Amer
• 金额: $ 74.94万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649990
• 关键词: 2019-nCoV; Amplifiers; Autoantibodies; Biology; Blood Vessels; Body Weight decreased; Brain; CASP4 gene; COVID-19; COVID-19 morbidity; COVID-19 patient; COVID-19 prevention; COVID-19 severity; COVID-19 treatment; CXCL1 gene; Cardiac; Caspase; Cell Death; Cells; Chemicals; Disease; Generations; Genetic; Genetic Polymorphism; Health; Heart; Heart Diseases; Human; IFNAR1 gene; Immune; Immune Targeting; Immunocompetent; Immunologic Deficiency Syndromes; Immunology; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Integral Membrane Protein; Interferon Type I; Interferons; Knock-out; Knockout Mice; Link; LoxP-flanked allele; Lung; Lung diseases; Lung infections; Mediating; Modeling; Molecular; Mus; Myocardial dysfunction; Natural Immunity; Neutrophil Infiltration; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Population; Positioning Attribute; Predisposition; Primary Cell Cultures; Production; Proteins; Pulmonary Pathology; Research Personnel; Risk Factors; Role; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Sampling; Signal Transduction; Swab; System; Testing; Therapeutic; Therapeutically Targetable; Thrombosis; Tissues; Vaccines; Variant; Vascular Endothelium; Viral; Virus; Virus Diseases; Virus Replication; Work; angiogenesis; antiviral immunity; cell type; chemokine; combat; cytokine; cytokine release syndrome; experience; heart damage; immune activation; inhibitor; interferon alpha receptor; lung injury; migration; mortality; mouse model; multiorgan damage; neutralizing antibody; neutrophil; prevent; pulmonary vascular remodeling; recruit; respiratory; risk variant; severe COVID-19; systemic inflammatory response; therapeutic target; viral entry inhibitor; virology

SUMMARY This project aims to mechanistically understand and combat pathological mechanisms activated by SARS- CoV-2 in the lungs and heart. We will further investigate whether these mechanisms are altered in specific immunodeficiencies linked to severe COVID-19. Our work will leverage major discoveries made by our group, including that the non-canonical inflammasome protein Caspase-11 (CASP11, homologous to CASP4 in humans) promotes pathological inflammation in SARS-CoV-2 infection, and that CASP11 KO mice experience significantly less severe infections than than WT mice. In Aim 1, we will test the hypothesis that cell-specific roles of CASP11 mediate SARS-CoV-2 pathogenesis by examining infections of cell-specific CASP11 KO mice (CASP11 flox allele mice). Further, we will target CASP11 downstream effectors identified by our work, such as the chemokine CXCL1 and recruited neutrophils, to determine their roles in unique aspects of SARS-CoV-2 pathogenesis. We will examine additional emergent candidate CASP11-dependent molecules, using genetic, neutralizing antibody, and chemical inhibitor strategies. This aim will yield new understanding of roles for CASP11 in specific cell types and will identify tailored strategies for preventing or treating unique aspects of COVID-19 pathology. In Aim 2, we will test the hypothesis that CASP11-dependent mechanisms of pathogenesis are exacerbated in specific immunodeficiencies linked to severe COVID-19. These include type I interferon (IFN) and IFN-induced transmembrane protein 3 (IFITM3) deficiencies. We have shown IFN alpha receptor KO and IFITM3 KO mice model these deficiencies, including exacerbated lung infections and virus dissemination to the heart. The use of these models in combination with CASP11 KOs will allow identification of pathogenic mechanisms in the lungs, and in the hearts of mice with or without direct cardiac tissue infection. Overall, our work will reveal fundamental mechanisms of SARS-CoV-2 pathogenesis in the lungs and heart, including involvement of specific cell types, pathways, and molecules, thus revealing targetable therapeutic strategies for combating COVID-19 in immunocompetent, as well as highly vulnerable, populations.

摘要 该项目旨在从机械上了解和对抗SARS激活的病理机制- 肺脏和心脏中有CoV-2病毒。我们将进一步调查这些机制是否在特定情况下被改变 免疫缺陷与严重的新冠肺炎有关。我们的工作将利用我们团队的重大发现， 包括非典型炎症体蛋白Caspase-11(CASP11，与CASP4同源) 人类)促进SARS-CoV-2感染的病理炎症，CASP11 KO小鼠经历 感染严重程度明显低于WT小鼠。在目标1中，我们将测试特定于细胞的假设 CASP11在细胞特异性CASP11 KO小鼠感染中的作用 (CASP11 Flox等位基因小鼠)。此外，我们将针对我们的工作确定的CASP11下游效应器，如 作为趋化因子CXCL1和招募的中性粒细胞，以确定它们在SARS-CoV-2独特方面的作用 发病机制。我们将研究其他新出现的依赖CASP11的候选分子， 中和抗体和化学抑制剂策略。这一目标将产生对以下角色的新理解 CASP11在特定的细胞类型中的作用，并将确定针对特定方面的预防或治疗独特的 新冠肺炎病理。在目标2中，我们将检验CASP11依赖机制的假设 与严重新冠肺炎相关的特异性免疫缺陷会加剧发病机制。其中包括第一类 干扰素及干扰素诱导的跨膜蛋白3缺乏症。我们已经展示了干扰素α 受体KO和IFITM3KO小鼠模拟这些缺陷，包括加重的肺部感染和病毒 传播到内心。将这些模型与CASP11 KO结合使用将使识别成为可能 有或没有直接心脏组织感染的小鼠的肺部和心脏的致病机制。 总体而言，我们的工作将揭示SARS-CoV-2在肺和心脏致病的基本机制， 包括特定细胞类型、途径和分子的参与，从而揭示有针对性的治疗 在免疫能力强和高度脆弱的人群中抗击新冠肺炎的战略。