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Survival of influenza A virus infected cells and effects on pathogenesis

甲型流感病毒感染细胞的存活及其对发病机制的影响

基本信息

批准号：
9188524
负责人：
Nicholas S Heaton
金额：
$ 10.45万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188524
关键词：
Acute Acute respiratory infection Address Antiviral Response Apoptosis Basic Science Cell Survival Cells Cellular Structures Clara cell Darkness Data Disease Disease Outbreaks Dissection Engineering Enterobacteria phage P1 Cre recombinase Epigenetic Process Epithelial Cells Excision FDA approved Genes Genetic Genetic Transcription Goals Immune response Infection Infiltration Influenza Influenza A virus Injury Interferons Intervention Label Lead Light Lung MicroRNAs Morbidity - disease rate Mus Nature Necrosis Pathogenesis Pathogenicity Phenotype Population Property Proteins Pulmonary Pathology RNA Reporter Research Resolution Respiratory tract structure Retroviridae System Techniques Testing Toxin Transgenic Mice Transgenic Organisms Up-Regulation Vaccines Viral Viral Genome Viral Pathogenesis Virulent Virus Virus Diseases base cell type chemokine design experimental study fluorophore genetic manipulation human disease immunoregulation in vivo influenzavirus interest lung injury lung repair mortality novel novel therapeutic intervention pandemic disease pathogen public health relevance receptor response retroviral transduction virtual virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): We are broadly interested in the mechanisms of influenza A virus induced disease. We have developed a novel in vivo reporter system with which to label cells that become infected. Importantly, these cells continue to express the reporter even if the virus is eventually cleared from the infected cell. Using this system, we have identified a lung epithelial cell type (club cells) that can become infected, and then clear and survive viral infection. In our preliminary data, we have shown that these cells are highly sensitive to interferon stimulation. Surviving cells also have highly up-regulated expression of chemokines, and that specific depletion or removal of these surviving cells positively influences lung repair after virally induced injury. This proposal will test two major questions: 1) Why are club cells uniquely able to survive direct viral infection (Aim 1) and 2) How are surviving cells influencing lung pathology during viral infection (Aim 2). Aim 1 details experiments designed to understand how club cells are surviving infection by characterizing the nature of the interferon stimulated gene (ISG) response during viral stimulation. We will not only look at the transcriptional and epigenetic factors influencing the increased ISG response, but also define which ISGs are the most important for influencing cellular survival. Aim 2 proposes to study how surviving cells are contributing to viral pathogenesis. We will genetically manipulate surviving cells in vivo to modulate their ability to secrete immunomodulatory factors. We will also directly neutralize the factors secreted by surviving club cells. This is the first description of cells tha can survive acute influenza virus infection, and the experiments in this proposal will increase our understanding of the mechanisms underlying cell survival as well as how these cells contribute to viral pathogenesis. Not only are these important questions for understanding the basic science of how viruses induce disease, but may also provide the basis of novel therapeutic intervention strategies targeting surviving cell populations.