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:
  • 金额:
    $ 66.54万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Respiratory viruses and the inflammasome: The double-edged sword of inflammation.
  • DOI:
    10.1371/journal.ppat.1011014
  • 发表时间:
    2022-12
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
  • 通讯作者:
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Steven M Varga其他文献

Steven M Varga的其他文献

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{{ truncateString('Steven M Varga', 18)}}的其他基金

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
  • 批准号:
    10388682
  • 财政年份:
    2022
  • 资助金额:
    $ 66.54万
  • 项目类别:
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
  • 批准号:
    10807884
  • 财政年份:
    2022
  • 资助金额:
    $ 66.54万
  • 项目类别:
RSV-induced inflammation in the brain
RSV 诱发的大脑炎症
  • 批准号:
    10252048
  • 财政年份:
    2020
  • 资助金额:
    $ 66.54万
  • 项目类别:
Balancing protection versus immunopathology by RSV-specific memory CD8 T cells
RSV 特异性记忆 CD8 T 细胞平衡保护与免疫病理学
  • 批准号:
    9977905
  • 财政年份:
    2017
  • 资助金额:
    $ 66.54万
  • 项目类别:
Role of TLR4 in Coronavirus Infection
TLR4 在冠状病毒感染中的作用
  • 批准号:
    7860303
  • 财政年份:
    2009
  • 资助金额:
    $ 66.54万
  • 项目类别:
Immunopathology mediated by RSV-specific CD4 T cells
RSV 特异性 CD4 T 细胞介导的免疫病理学
  • 批准号:
    7895292
  • 财政年份:
    2009
  • 资助金额:
    $ 66.54万
  • 项目类别:
Role of TLR4 in Coronavirus Infection
TLR4 在冠状病毒感染中的作用
  • 批准号:
    7701085
  • 财政年份:
    2009
  • 资助金额:
    $ 66.54万
  • 项目类别:
Immunopathology mediated by RSV-specific CD4 T cells
RSV 特异性 CD4 T 细胞介导的免疫病理学
  • 批准号:
    7568970
  • 财政年份:
    2007
  • 资助金额:
    $ 66.54万
  • 项目类别:
Immunopathology mediated by RSV-specific CD4 T cells
RSV 特异性 CD4 T 细胞介导的免疫病理学
  • 批准号:
    8013503
  • 财政年份:
    2007
  • 资助金额:
    $ 66.54万
  • 项目类别:
Immunopathology mediated by RSV-specific CD4 T cells
RSV 特异性 CD4 T 细胞介导的免疫病理学
  • 批准号:
    7758806
  • 财政年份:
    2007
  • 资助金额:
    $ 66.54万
  • 项目类别:

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