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Deciphering the complexities of inflammasome activation following RSV infection

破译 RSV 感染后炎症小体激活的复杂性

基本信息

批准号：
10655297
负责人：
Steven M Varga
金额：
$ 66.54万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655297
关键词：
Adaptive Immune System Address Animal Model Cell Reprogramming Cells Child Chimeric Proteins Clinical Data Disease Elderly Engineering Ethics Future Genes Glycolysis Goals Healthcare Human Immune Immune System Diseases Immune response Immunocompromised Host Impact evaluation In Vitro Individual Infant Infection Infiltration Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Interleukin-1 beta Interleukin-6 Knockout Mice Knowledge Licensing Link Lower Respiratory Tract Infection Lung Macrophage Mediating Metabolic Metabolism Multiprotein Complexes Mus Names Process Production Proteins Reagent Recombinants Reporting Respiration Respiratory Disease Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory System Respiratory syncytial virus Role Severity of illness Shapes Signal Transduction Testing Variant Virus adaptive immune response cytokine design in vivo insight interest mouse model neutrophil new therapeutic target recruit respiratory response therapeutic target vaccine candidate

项目摘要

Abstract Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in children, the elderly and immunocompromised individuals and there is currently no licensed RSV vaccine. The host inflammatory response is believed to contribute to disease severity following RSV infection. Much less is currently known regarding the role of RSV strains in modulating the host inflammatory response. The production of proinflammatory cytokines IL-1β and IL-6 have been found to be significantly increased in the respiratory tract of infants with severe disease. In addition, RSV infection has been reported to promote hypermetabolism in the upper respiratory cells of RSV-infected children. IL-1β is a key proinflammatory cytokine and its secretion is tightly regulated by multi-protein complexes named inflammasomes. Activation of the inflammasome is a two- step process, including priming and activation steps, that requires metabolic reprogramming of the cell. Previous studies have demonstrated that RSV A2 infection induces the activation of the NLRP3 inflammasome. Our preliminary data illustrate that infection with the RSV 2-20 strain results in significantly increased IL-1β production as compared to infection with the A2 strain. We also observe an increase in glycolysis in RSV 2-20 infected macrophages as compared to A2 infected macrophages. Unexpectedly, when we infect cells with a recombinant RSV A2 strain engineered to express the 2-20 fusion (F) protein, termed A2/2-20F, we observe a significant increase in both IL-1β production and glycolysis in macrophages. Thus, our exciting new preliminary data indicate that RSV strains differentially activate the inflammasome and this strain- dependent increased inflammasome activation is mediated by the F protein. Thus, important knowledge gaps exist regarding how RSV-derived genes modulate the host inflammatory response. Our long-term goal is to understand the virus-derived factors that modulate the host immune response and disease severity following RSV infection. The objective of this application is to determine the changes that occur in inflammasome signaling and metabolism following RSV infection. Moreover, we will explore how these changes impact innate cell recruitment into the lung and shape the subsequent adaptive immune response. Our central hypothesis is that the RSV 2-20 strain enhances both inflammasome priming and activation signals resulting in increases in both neutrophil influx and the Th17 response. We will achieve the goals outlined above by pursuing the following two specific aims: Aim 1. Determine the mechanism of RSV F protein-mediated inflammasome activation. Aim 2. Examine the role of differential inflammasome activation on immune cell recruitment and disease following RSV infection. The knowledge gained from these studies will provide a mechanistic understanding of RSV-mediated inflammatory responses. In addition, these studies will greatly impact the evaluation of therapeutic targets and design of future RSV vaccine candidates.

摘要