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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：
10615162
负责人：
Andrew Atwell Oberst
金额：
$ 22.06万
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/10615162
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Adaptive Immune System Affect Antigens Apoptosis Architecture Attention Atypical lymphocyte Autoimmunity COVID-19 COVID-19 mortality COVID-19 patient COVID-19/ARDS Cell Death Cell Death Induction Cell Death Process Cell membrane Cells Cessation of life Clinical Coagulation Process Cytolysis Data Defense Mechanisms Disease Epithelial Cells Epithelium Event Functional disorder Future Genetic Transcription Heterogeneity Hour Human Hyperactivity Illness Days Image Immune Immune response Immune system Immunofluorescence Immunologic Immunologics Infection Inflammation Inflammatory Inflammatory Response Innate Immune System Lung Lung infections Lymphocyte Lymphocyte Activation 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 chemokine 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.

项目总结