Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections

病毒感染中的硫化氢和 NRF2 串扰

基本信息

  • 批准号:
    10379874
  • 负责人:
  • 金额:
    $ 50.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-01-11 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Respiratory syncytial virus (RSV) is a major cause of upper and lower respiratory tract infections (LRTIs) in children, elderly and immunocompromised hosts, for which no effective treatment or vaccine is available. Children who develop RSV-induced bronchiolitis are also at increased risk for recurrent wheezing and development of asthma in later life. Although the pathogenesis of RSV-induced disease remains a matter of intense scientific debate, increasing evidence from experimental models and studies in naturally acquired infections suggest that severe LRTIs are indeed associated with increased viral “load” and delayed viral clearance due to an innate immune response that fails to restrict viral replication, yet causing inflammation and tissue damage. The endogenously-generated gasotransmitter hydrogen sulfide (H2S) is implicated in a variety of inflammatory and vascular disorders, associated with both pro- and anti-inflammatory signaling. Recently, our group has gathered important new data, reagents and animals models that demonstrate a key role of H2S in mediating antiviral and anti-inflammatory responses in the lung. In particular, we have shown that H2S potently inhibits viral replication, exerts anti-inflammatory activity, and controls airway hyperresponsiveness in RSV-infected mice. At the cellular level, we have shown that RSV is capable of inhibiting the expression of cystathionine γ-lyase (CSE), the key enzyme that generates H2S is the lung, reducing the ability to generate cellular H2S. We propose that dysregulation of the H2S pathway affects host antiviral response and plays a critical role in the pathogenesis of severe RSV infections. Our findings indicate an important cross-talk between H2S and the transcription factor NF-E2-related factor 2 (NRF2)-dependent pathways, which control the cellular redox balance, each of them exerting a positive influence on the other, and both of them being downregulated in the course of RSV infection. Thus, in this project, we will test the central hypothesis that inhibition of cytoprotective H2S generation, due to decreased NRF2-dependent gene transcription, leads to clinical manifestations of RSV infection. We will employ a combination of in vitro and in vivo approaches to test this hypothesis, by the use of cells and mice genetically deficient in either NRF2 or H2S generating enzymes, and the access to our ongoing cohort of infants and young children with primary RSV infections. This project will elucidate innate pathways by which respiratory viruses modulate lung disease, with strong implications for developing novel antiviral and anti-inflammatory therapeutic strategies for RSV-induced LRTI and possibly long-term consequences, such as recurrent wheezing or asthma. Our long-standing clinical and research expertise in the area of pathogenesis of viral bronchiolitis and RSV infections, strong preliminary data, and UTMB's outstanding resources in the area of lung disease make us ideally suited to pursue this innovative project.
项目总结/文摘

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)

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Antonella Casola其他文献

Antonella Casola的其他文献

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{{ truncateString('Antonella Casola', 18)}}的其他基金

PIWIL4 and piRNAs in RSV Infection
RSV 感染中的 PIWIL4 和 piRNA
  • 批准号:
    10667951
  • 财政年份:
    2023
  • 资助金额:
    $ 50.38万
  • 项目类别:
Role of Hypoxia-Inducible Factors (HIFs) in Respiratory Syncytial Virus Infection
缺氧诱导因子 (HIF) 在呼吸道合胞病毒感染中的作用
  • 批准号:
    10742170
  • 财政年份:
    2023
  • 资助金额:
    $ 50.38万
  • 项目类别:
Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections
病毒感染中的硫化氢和 NRF2 串扰
  • 批准号:
    9911341
  • 财政年份:
    2019
  • 资助金额:
    $ 50.38万
  • 项目类别:
Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections
病毒感染中的硫化氢和 NRF2 串扰
  • 批准号:
    9843442
  • 财政年份:
    2017
  • 资助金额:
    $ 50.38万
  • 项目类别:
A novel role of NF-kB in viral-induced airway oxidative stress
NF-kB 在病毒诱导的气道氧化应激中的新作用
  • 批准号:
    8784185
  • 财政年份:
    2013
  • 资助金额:
    $ 50.38万
  • 项目类别:
A novel role of NF-kB in viral-induced airway oxidative stress
NF-kB 在病毒诱导的气道氧化应激中的新作用
  • 批准号:
    8638667
  • 财政年份:
    2013
  • 资助金额:
    $ 50.38万
  • 项目类别:
Innate Immune Response to Human Metapneumovirus Infection
对人类偏肺病毒感染的先天免疫反应
  • 批准号:
    7785949
  • 财政年份:
    2010
  • 资助金额:
    $ 50.38万
  • 项目类别:
Innate Immune Response to Human Metapneumovirus Infection
对人类偏肺病毒感染的先天免疫反应
  • 批准号:
    8661692
  • 财政年份:
    2010
  • 资助金额:
    $ 50.38万
  • 项目类别:
Innate Immune Response to Human Metapneumovirus Infection
对人类偏肺病毒感染的先天免疫反应
  • 批准号:
    8473152
  • 财政年份:
    2010
  • 资助金额:
    $ 50.38万
  • 项目类别:
Innate Immune Response to Human Metapneumovirus Infection
对人类偏肺病毒感染的先天免疫反应
  • 批准号:
    8282740
  • 财政年份:
    2010
  • 资助金额:
    $ 50.38万
  • 项目类别:

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