Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

摘要 肺炎是由细菌和/或病毒引起的，是全世界儿童死亡的主要原因。 先前的病毒疾病与流感感染有关，是与继发性细菌有关的主要危险因素。 肺炎。流感感染是全世界发病率和死亡率的年度季节性原因。 严重的流感肺炎通常会因细菌感染而恶化，导致患者预后不良。 那些既有肺部疾病和以前健康的人。流感大流行的可能性 病毒增加了了解疾病发病机制的重要性。此外，次生细菌 金黄色葡萄球菌肺炎的患病率正在上升，而抗生素耐药性仍在继续 传播。这项应用的重点是了解流感诱导的机制 对细菌双重感染的易感性，这是大流行爆发期间死亡的主要原因。在.期间 在之前的资助期，我们的实验室已经确定了抑制细菌诱导的17型免疫 在流感之前作出反应是一种关键的易感机制。我们已在 在此背景下阐明异常寄主防御途径的领域。在此续订应用程序中，我们将构建 根据我们正在进行的工作，从最初的焦点衍生出三个非常新颖的目标。我们假设S。 流感病毒诱导的STAT2负性调节金黄色葡萄球菌诱导的17型先天免疫激活 信号和ASC炎症小体。此外，我们建议外源性抗菌肽(AMP)治疗 提出了一种治疗流感、细菌重叠感染的新策略。在目标1中，我们将确定 流感期间STAT2信号抑制金黄色葡萄球菌抗菌宿主防御的机制(S) 超级感染。目标2将集中于ASC炎症小体敲除小鼠的机制(S)。 防止继发性金黄色葡萄球菌感染恶化。在目标3中，我们将研究 流感期间金黄色葡萄球菌外源性AMP的产生及其治疗潜力的评价 感染。拟议的研究将进一步加深我们对流感如何损害后续免疫力的理解。 针对金黄色葡萄球菌(目标1)，如何在肺部启动对金黄色葡萄球菌的免疫反应(目标2)，并测试 控制流感后继发性细菌性肺炎的新治疗方法(目标3)。我们的 压倒一切的目标是了解流感易感性的关键机制(S)，金黄色葡萄球菌超. 并在疾病的临床前模型中提供新的治疗靶点。

SUMMARY Pneumonia, caused by bacterial and/or viral etiology, is the leading cause of death in children worldwide. Preceding viral illness, linked to influenza infection, is a primary risk factor associated with secondary bacterial pneumonia. Influenza infection is an annual, seasonal cause of morbidity and mortality throughout the world. Severe influenza pneumonia is often exacerbated by bacterial infection resulting in poor patient outcomes in those with preexisting lung morbidity and in previously healthy individuals. The pandemic potential of influenza viruses heightens the importance of understanding disease pathogenesis. Further, secondary bacterial pneumonia with Staphylococcus aureus is increasing in prevalence, while antibiotic resistance continues to propagate. The focus of this application is upon understanding the influenza-induced mechanisms of susceptibility to bacterial super-infection, the leading cause of death during pandemic outbreaks. During the previous funding period, our laboratory has identified suppression of bacterial-induced Type 17 immune responses by preceding influenza as a critical susceptibility mechanism. We have published extensively in the area of elucidating aberrant host defense pathways in this context. In this renewal application, we will build upon our ongoing work with three highly novel Aims derived from the original focus. We hypothesize that S. aureus-induced Type 17 innate immune activation is negatively regulated by influenza-induced STAT2 signaling and the Asc inflammasome. Further, we propose that exogenous antimicrobial peptide (AMP) therapy presents a novel therapeutic strategy in influenza, bacterial super-infection. In Aim 1 we will determine the mechanism(s) by which STAT2 signaling impairs anti-bacterial host defense against S. aureus during influenza super-infection. Aim 2 will focus on the mechanism(s) by which Asc inflammasome knockout mice are protected from exacerbation of secondary S. aureus infection. In Aim 3 we will investigate the mechanism of AMP production and evaluate the therapeutic potential of exogenous AMPs during influenza, S. aureus super- infection. The proposed studies will further our understanding of how influenza impairs subsequent immunity against S. aureus (Aim 1), how the immune response to S. aureus is initiated in the lung (Aim 2), and test novel therapeutic approaches for controlling post-influenza secondary bacterial pneumonia (Aim 3). Our overriding goal is to understand the critical mechanism(s) of susceptibility to influenza, S. aureus super- infection and provide novel treatment targets in a pre-clinical model of disease.