The role of ACE2 in Influenza viral infection mediated immune compromise and subsequent bacterial lung infection

ACE2在流感病毒感染介导的免疫损害和随后的细菌性肺部感染中的作用

基本信息

  • 批准号:
    10393014
  • 负责人:
  • 金额:
    $ 54.68万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-15 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Project Summary Overall goal of this application is to advance our understanding of ACE2 biology in the lung, to explore a novel link between ACE2 activity and the interferon-γ-mediated compromised innate immunity in IAV and subsequent bacterial lung infection, and to lay the groundwork for a new strategy to prevent and treat lethal IAV-bacterial coinfection by manipulating ACE2 activity. Infection with secondary bacterial pathogens is the primary cause of excess mortality during influenza A virus (IAV) outbreaks. Novel therapies that modulate host immunity are urgently needed. Moreover, compelling evidence indicates that the immune defects caused by IAV infection are responsible for the severe secondary bacterial lung infection. These include impaired neutrophil influx due to sustained desensitization and the induction of an immune-suppressive state of the lung. The renin-angiotensin system (RAS) is constitutively activated to maintain blood pressure and to mount a host defense to invading microbes. However, overactive RAS facilitates exacerbated inflammatory response, while repressive RAS curbs host defense. Thus, regulation of optimal RAS signaling may represent a novel therapeutic strategy in a bacterial lung infection. Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator of the RAS activation. Our preliminary studies in a mouse model of IAV-bacterial coinfection indicate that pulmonary ACE2 is dynamically regulated during IAV infection and peaked around 6 dpi. Interestingly, the IAV induced interferon- γ induces ACE2 expression. We also find that the elevated pulmonary ACE2 activity at the time of secondary bacterial infection mitigates neutrophilic inflammation and increases the severity of the secondary bacterial infection. The observation raises the possibility that the IAV infection induced ACE2 activity, partially by interferon- γ, predispose the mice to secondary bacterial lung infection by attenuating neutrophilic inflammatory response. Our overall hypothesis is that is that ACE2 plays a pivotal role in the IAV induced-IFN- γ mediated immune compromise, thus contributes to the pathogenesis of secondary bacterial lung infection post IAV, and that optimal strategy to manipulate active ACE2 will improve the outcome of IAV-bacterial coinfection. We propose the following aims: Aim1. To investigate the role and mechanism of IFN- γ induced pulmonary ACE2 in IAV-bacterial coinfection. manipulate active ACE2 will improve the outcome of IAV-bacterial coinfection. Aim2. To elucidate the mechanisms through which pulmonary ACE2 modulates neutrophil influx in IAV-bacterial coinfection. Aim3. To evaluate the preventive and interventional strategies to IAV-bacteria co-infection by monitoring serum and manipulating pulmonary ACE2 activity. These studies will make a significant conceptual advance and pre-clinical insight by defining the role and therapeutic potential of ACE2 in IAV-bacterial lung disease.
项目概要 该应用的总体目标是增进我们对肺部 ACE2 生物学的理解,探索一种 IAV 和 IAV 中 ACE2 活性与干扰素 γ 介导的先天免疫受损之间的新联系 随后的细菌性肺部感染,并为预防和治疗致命的新策略奠定基础 通过操纵 ACE2 活性实现 IAV-细菌共感染。继发细菌病原体感染是 甲型流感病毒(IAV)爆发期间死亡率过高的主要原因。调节宿主的新疗法 迫切需要免疫力。此外,令人信服的证据表明,IAV 引起的免疫缺陷 感染是造成严重继发性细菌性肺部感染的原因。这些包括中性粒细胞流入受损 由于持续脱敏和诱导肺部免疫抑制状态。肾素-血管紧张素 系统(RAS)被组成性激活以维持血压并启动宿主防御入侵 微生物。然而,过度活跃的 RAS 会加剧炎症反应,而抑制 RAS 则会抑制宿主的炎症反应。 防御。因此,最佳 RAS 信号传导的调节可能代表细菌肺的一种新的治疗策略 感染。血管紧张素转换酶 2 (ACE2) 是 RAS 激活的有效负调节因子。我们的 IAV-细菌共感染小鼠模型的初步研究表明,肺 ACE2 动态变化 IAV 感染期间受到调节,并在 6 dpi 左右达到峰值。有趣的是,IAV 诱导的干扰素-γ 诱导 ACE2 表达。我们还发现继发细菌感染时肺部 ACE2 活性升高 减轻中性粒细胞炎症并增加继发细菌感染的严重程度。观察结果 提出了 IAV 感染诱导 ACE2 活性(部分是通过干扰素-γ)的可能性,使小鼠易于 通过减弱中性粒细胞炎症反应继发细菌性肺部感染。我们的总体假设是 也就是说,ACE2 在 IAV 诱导的 IFN-γ 介导的免疫损害中发挥着关键作用,从而有助于 IAV 后继发细菌性肺部感染的发病机制,以及控制的最佳策略 活跃的 ACE2 将改善 IAV 细菌合并感染的结果。我们提出以下目标: 目标1。探讨IFN-γ诱导的肺ACE2在IAV-细菌合并感染中的作用和机制。 操纵活性 ACE2 将改善 IAV 细菌合并感染的结果。目标2。阐明机制 肺 ACE2 通过其调节 IAV 细菌合并感染中的中性粒细胞流入。目标3。评估 通过监测血清和控制IAV-细菌混合感染的预防和干预策略 肺 ACE2 活性。 这些研究将通过定义作用和作用来取得重大的概念进步和临床前洞察力。 ACE2 在 IAV 细菌性肺病中的治疗潜力。

项目成果

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Hongpeng Jia其他文献

Hongpeng Jia的其他文献

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{{ truncateString('Hongpeng Jia', 18)}}的其他基金

The role of ACE2 in Influenza viral infection mediated immune compromise and subsequent bacterial lung infection
ACE2在流感病毒感染介导的免疫损害和随后的细菌性肺部感染中的作用
  • 批准号:
    10165489
  • 财政年份:
    2020
  • 资助金额:
    $ 54.68万
  • 项目类别:
Supplement to "New ACE2 activator and its prodrug as novel therapeutic regents for inflammatory pulmonary diseases"
“新型 ACE2 激活剂及其前药作为炎症性肺部疾病的新型治疗药物”的补充
  • 批准号:
    10265687
  • 财政年份:
    2020
  • 资助金额:
    $ 54.68万
  • 项目类别:
The role of ACE2 in Influenza viral infection mediated immune compromise and subsequent bacterial lung infection
ACE2在流感病毒感染介导的免疫损害和随后的细菌性肺部感染中的作用
  • 批准号:
    10609817
  • 财政年份:
    2020
  • 资助金额:
    $ 54.68万
  • 项目类别:

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