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.

项目摘要 为了更好地了解严重COVID 19的决定因素，我们专注于炎性小体调节 蛋白DPP 9。GWAS已经将DPP 9与COVID 19的不良结局和特发性 肺纤维化。DPP 9和密切相关的DPP 8作为病毒炎性体的内源性抑制剂 传感器NLRP 1和CARD 8。该途径被多种病原体感知机制激活， 包括检测病毒编码蛋白酶、细菌E3泛素连接酶和直接感测病毒dsRNA。 我们的初步数据表明，这种途径在人类骨髓细胞中转录上调， 对SARS-CoV-2的反应，这是一种激活炎性小体的刺激。我们还发现老鼠 缺乏Dpp 8和Dpp 9的人，T细胞反应失调， 用SARS-CoV-2挑战。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DPP 9内含子区域内的COVID 19风险等位基因rs 2109069“A”赋予，2）T细胞的基础 我们的新型小鼠模型中的调节异常和3）T细胞功能障碍如何影响疾病的严重程度， SARS-CoV-2感染。