Investigation of Dpp9 in COVID19

COVID19 中 Dpp9 的调查

• 批准号: 10725833
• 负责人: Richard A. Flavell
• 金额: $ 24.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725833
• 关键词: 2019-nCoV; Biological Assay; COVID-19; COVID-19 risk; COVID-19 severity; COVID-19 susceptibility; Cell Death; Cells; Cessation of life; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Disease Outcome; Double-Stranded RNA; Effectiveness; Failure; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Human; Human Genetics; Humoral Immunities; Hyperactivity; Immune; Immune response; Immunity; Immunologics; Individual; Inflammasome; Inflammatory; Investigation; K-18 conjugate; Knowledge; Lung; Mediating; Mus; Myeloid Cells; Outcome; Pathway interactions; Peptide Hydrolases; Phenotype; Physiology; Population; Respiratory distress; Role; SARS-CoV-2 infection; Severity of illness; Stimulus; Susceptibility Gene; T cell response; T-Lymphocyte; Testing; Vaccination; Vaccines; Viral; Virus; Virus Inhibitors; Work; adaptive immune response; comorbidity; coronavirus pandemic; cytokine; genetic regulatory protein; genome wide association study; global health; idiopathic pulmonary fibrosis; migration; monocyte; mouse model; novel; novel coronavirus; novel vaccines; pathogen; peripheral tolerance; pharmacologic; protein complex; respiratory virus; response; risk variant; sensor; severe COVID-19; ubiquitin-protein ligase; viral detection

Project Summary To better understand the determinants of severe COVID19, we have focused on the inflammasome regulatory protein DPP9. GWAS have implicated DPP9 in poor outcomes in COVID19 and in the development of idiopathic pulmonary fibrosis. DPP9 and closely related DPP8 serve as endogenous inhibitors of the viral inflammasome sensors NLRP1 and CARD8. This pathway is activated by diverse mechanisms of pathogen sensing which include detection of viral encoded proteases, bacterial E3 ubiquitin ligases and direct sensing of viral dsRNA. Our preliminary data indicate that this pathway is transcriptionally upregulated in human myeloid cells in response to SARS-CoV-2, a stimulus which activates the inflammasome. We have also discovered that mice which lack Dpp8 and Dpp9 have dysregulated T cell responses and develop more severe disease when challenged with SARS-CoV-2. Our ongoing work seeks to better understand 1) the immunological differences conferred by the COVID19 risk allele rs2109069 “A” located within a DPP9 intronic region, 2) the basis for T cell dysregulation in our novel mouse model and 3) how T cell dysfunction influences disease severity in response to SARS-CoV-2 infection.

项目概要 为了更好地了解严重 COVID19 的决定因素，我们重点关注炎症小体调控 蛋白质 DPP9。GWAS 表明 DPP9 与 COVID19 的不良结局和特发性的发展有关。 DPP9 和密切相关的 DPP8 作为病毒炎症小体的内源性抑制剂。 传感器 NLRP1 和 CARD8 该通路由多种病原体感应机制激活。 包括病毒编码蛋白酶、细菌 E3 泛素连接酶的检测和病毒 dsRNA 的直接传感。 我们的初步数据表明，该途径在人骨髓细胞中转录上调 我们还发现小鼠对 SARS-CoV-2 的反应，这是一种激活炎症小体的刺激。 缺乏 Dpp8 和 Dpp9 的 T 细胞反应失调，并在以下情况下发展为更严重的疾病： 我们正在进行的工作旨在更好地了解 1) 免疫学差异。 由位于 DPP9 内含子区域内的 COVID19 风险等位基因 rs2109069“A”赋予，2) T 细胞的基础 我们的新型小鼠模型中的失调以及 3) T 细胞功能障碍如何影响疾病的严重程度 SARS-CoV-2 感染。