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.

抽象的呼吸道合胞病毒（RSV）是儿童，年龄较大和免疫功能低下的个体，目前没有许可的RSV疫苗。宿主炎症据信，反应在RSV感染后导致疾病严重程度。目前已知要少得多关于RSV菌株在调节宿主炎症反应中的作用。生产促炎细胞因子IL-1β和IL-6在呼吸道中显着增加患有严重疾病的婴儿。此外，据报道，RSV感染促进了超定代谢 RSV感染儿童的上呼吸道细胞。 IL-1β是关键促炎细胞因子，其分泌是由名为炎症的多蛋白质复合物严格调节。炎性体的激活是两个步骤过程，包括启动和激活步骤，需要对细胞的代谢重编程。先前的研究表明，RSV A2感染诱导了NLRP3的激活炎症。我们的初步数据说明了RSV 2-20菌株的感染显着导致与A2菌株感染相比，IL-1β产生增加。我们还观察到增加与A2感染的巨噬细胞相比，RSV 2-20感染的巨噬细胞中的糖酵解。出乎意料的是，什么时候我们用重组RSV A2菌株感染细胞，该菌株被设计为表达2-20融合（F）蛋白的细胞 A2/2-20F，我们观察到巨噬细胞中IL-1β产生和糖酵解的显着增加。那，我们的令人兴奋的新初步数据，表明RSV菌株会不同地激活炎症体和该菌株 - 依赖性增加的炎性体激活是由F蛋白介导的。这是重要的知识差距存在有关RSV衍生的基因如何调节宿主炎症反应的存在。我们的长期目标是了解调节宿主免疫响应和疾病严重程度的病毒衍生因素 RSV感染。该应用的目的是确定炎症体中发生的变化 RSV感染后的信号传导和代谢。此外，我们将探讨这些变化如何影响先天细胞募集到肺部并塑造随后的适应性免疫反应。我们的中心假设是 RSV 2-20菌株增强了炎性体启动和激活信号，导致增加中性粒细胞的影响和TH17反应。我们将通过追求上述目标来实现上述目标以下两个具体目的：目标1。确定RSV F蛋白介导的炎症体的机制激活。目标2。检查不同炎症体激活在免疫细胞募集和 RSV感染后的疾病。从这些研究中获得的知识将提供机械了解RSV介导的炎症反应。此外，这些研究将极大地影响评估治疗靶标和未来RSV疫苗候选物的设计。