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

项目摘要 本申请的总体目标是促进我们对肺中ACE 2生物学的理解，探索肺中ACE 2的表达。 IAV中ACE 2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性肺部感染的新策略奠定基础。 通过操纵ACE 2活性的IAV-细菌共感染。继发性细菌病原体感染是 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 感染是导致严重的继发性细菌性肺部感染的原因。这些包括受损的中性粒细胞流入 这是由于持续的脱敏和肺的免疫抑制状态的诱导。肾素-血管紧张素 RAS系统（RAS）被组成性激活以维持血压并对入侵进行宿主防御 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抑制了宿主的炎症反应。 防御因此，最佳RAS信号的调节可能代表细菌肺中的新治疗策略 感染血管紧张素转换酶2（ACE 2）是RAS激活的有效负调节剂。我们 在IAV-细菌共感染的小鼠模型中的初步研究表明，肺ACE 2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ACE 2 表情我们还发现继发性细菌感染时肺ACE 2活性升高， 减轻嗜中性炎症并增加继发性细菌感染的严重性。观察 IAV感染诱导ACE 2活性的可能性，部分是通过干扰素- γ，使小鼠易于 继发性细菌性肺部感染通过减弱嗜酸性炎症反应。我们的总体假设是 即ACE 2在IAV诱导的IFN- γ介导的免疫损害中起关键作用，从而有助于 IAV后继发性细菌性肺部感染的发病机制，以及操作的最佳策略 活性ACE 2将改善IAV-细菌混合感染的结局。我们提出以下目标： 目标1.目的探讨IFN- γ诱导的肺ACE 2在IAV-细菌混合感染中的作用及机制。 控制活性ACE 2可改善IAV-细菌共感染的结局。目标2。为了阐明 肺ACE 2通过其调节IAV-细菌共感染中的中性粒细胞流入。目标3。评价 通过血清监测和操作干预，预防和干预IAV-细菌混合感染 肺ACE 2活性。 这些研究将通过定义作用和 ACE 2在IAV细菌性肺病中的治疗潜力。

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.