Activation of inflammatory programmed cell death by SARS-CoV-2

SARS-CoV-2 激活炎症性程序性细胞死亡

基本信息

批准号：
10450286
负责人：
Andrew Atwell Oberst
金额：
$ 26.48万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450286
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Adaptive Immune System Address Affect Antigens Apoptosis Architecture Attention Atypical lymphocyte COVID-19 COVID-19 mortality COVID-19 patient COVID-19/ARDS Cell Death Cell Death Process Cell membrane Cells Cessation of life Clinical Coagulation Process Cytolysis Data Defense Mechanisms Disease Epithelial Epithelial Cells Event Future Genetic Transcription Heterogeneity Hour Human Hyperactivity Illness Days Image Immune Immune response Immune system Immunofluorescence Immunologic Immunologics Infection Inflammation Inflammatory Inflammatory Response Lead Lung Lung infections Lymphocyte Measures Mediating Morphology Mus Nature Pathologic Pathology Patients Phosphotransferases Process Production Publications RIPK1 gene RIPK3 gene RNA Viruses Reaction Respiratory Tract Infections Role SARS-CoV-2 infection Severities Signal Pathway Signal Transduction Slice Suicide prevention System Testing Tissues Viral Virus Virus Diseases Virus Replication Work adaptive immune response alveolar epithelium antiviral immunity autoreactivity cell suicide cytokine cytokine release syndrome human tissue immune activation inhibitor molecular marker mouse model pandemic disease pathogen post SARS-CoV-2 infection preservation recruit response severe COVID-19 single cell sequencing suicidal morbidity

项目摘要

Project Summary Programmed cell death is an ancient and effective defense mechanism against intracellular infection: activation of cellular suicide in response to intracellular pathogens eliminates pathogens’ replicative niches and exposes them to immune-mediated killing. However, when these responses occur incorrectly or overexuberantly, they can cause tissue destruction and exacerbate inflammation. Work from many groups including our own has shown that infection of the lung with RNA viruses can trigger cell death via the inflammatory process termed “necroptosis.” Our preliminary data confirm that infection of cells of the lung epithelium with SARS-CoV-2 leads to their death by necroptosis. These findings, along with additional preliminary data contained within the proposal, lead us to hypothesize that cell death by necroptosis is a key early response to infection of the lung with SARS-CoV-2. We further hypothesize that while a measured necroptotic response helps to eliminate SARS-CoV-2 virus, excessive necroptosis in the lung can lead to detrimental inflammatory pathology. We will test these hypotheses by focusing on three Aims: First, we will carry out detailed immunological and pathological profiling of SARS-2 infected mice lacking key components of necroptotic signaling. Next, we will use a mouse model developed in our lab to experimentally induce necroptosis in the alveolar epithelium in conjunction with SARS-2 infection. Finally, we will use human lung slices to assess cell death responses to SARS-2 infection in intact human tissue.

项目概要程序性细胞死亡是一种古老而有效的细胞内感染防御机制：激活响应细胞内病原体的细胞自杀消除了病原体的复制生态位并暴露然而，当这些反应发生不正确或过度时，它们就会受到免疫介导的杀伤。可能会导致组织破坏和炎症恶化，包括我们自己在内的许多团体的工作。研究表明，RNA 病毒感染肺部可以通过称为“炎症”的过程引发细胞死亡。 “坏死性凋亡。”我们的初步数据证实，肺上皮细胞感染 SARS-CoV-2 会导致这些发现以及其中包含的其他初步数据。的建议，使我们认识到坏死性凋亡引起的细胞死亡是对感染的关键早期反应我们进一步认为，测定的坏死性凋亡反应有助于 SARS-CoV-2病毒，消除肺部过度坏死性凋亡可导致炎性炎症我们将通过关注三个目标来检验这些假设：首先，我们将进行详细的研究。缺乏坏死性凋亡关键成分的 SARS-2 感染小鼠的免疫学和病理学分析接下来，我们将使用我们实验室开发的小鼠模型来实验诱导坏死性凋亡。肺泡上皮与 SARS-2 感染的关系最后，我们将使用人肺切片来评估细胞。完整人体组织对 SARS-2 感染的死亡反应。