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

项目摘要 这项应用的总体目标是促进我们对ACE2在肺中生物学的理解，探索一种 血管紧张素转换酶2活性与干扰素-γ介导的先天性免疫低下之间的新联系 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 通过调控ACE2活性实现IAV-细菌共感染。感染继发性细菌病原体是 甲型流感病毒(IAV)暴发期间死亡率过高的主要原因。调节宿主的新疗法 我们迫切需要豁免权。此外，令人信服的证据表明，IAV引起的免疫缺陷 感染是导致严重继发性细菌性肺部感染的原因。这些包括中性粒细胞内流受损 由于持续的脱敏和肺部免疫抑制状态的诱导。肾素-血管紧张素 系统(RAS)被结构性地激活以维持血压和建立对入侵的宿主防御 微生物。然而，过度活跃的RAS促进了炎症反应的加剧，而抑制性RAS抑制了宿主 防守。因此，对最佳ras信号的调节可能代表了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激活的强有力的负性调节因子。我们的 在IAV-细菌混合感染小鼠模型中的初步研究表明，肺ACE2是动态的 在IAV感染期间调节，并在6dpi左右达到峰值。有趣的是，IAV诱导的干扰素-γ诱导血管紧张素转换酶2 表情。我们还发现，继发性细菌感染时肺血管紧张素转换酶2活性升高 减轻中性粒细胞炎症，增加继发性细菌感染的严重程度。观察到的 增加了IAV感染诱导ACE2活性的可能性，部分是通过干扰素-γ，使小鼠容易患上 通过减弱中性粒细胞炎症反应而导致继发性细菌性肺部感染。我们的总体假设是 也就是说，ACE2在IAV诱导的干扰素-γ介导的免疫妥协中起着关键作用，从而有助于 IAV后继发细菌性肺部感染的发病机制及最佳操作策略 活化的ACE2将改善IAV-细菌混合感染的结局。我们提出以下目标： 目的：1.目的：探讨干扰素-γ诱导的肺血管紧张素转换酶2在鸡传染性胸膜肺炎病毒-细菌混合感染中的作用及机制。 操纵活性ACE2将改善IAV-细菌混合感染的转归。AIM2.以阐明其作用机制 在IAV-细菌混合感染中，肺血管紧张素转换酶2通过其调节中性粒细胞内流。Aim3.要评估 通过血清监测和干预预防IAV-细菌混合感染的策略 肺血管紧张素转换酶2活性。 这些研究将在概念上取得重大进展，并通过定义角色和临床前洞察 血管紧张素转换酶2在IAV细菌性肺部疾病中的治疗潜力。

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.