Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

总结 由细菌和/或病毒病因引起的肺炎是全世界儿童死亡的主要原因。 先前的病毒性疾病，与流感感染有关，是继发性细菌感染的主要危险因素。 肺炎流感感染是全世界每年一次、季节性发病和死亡的原因。 严重的流感肺炎通常因细菌感染而加重，导致患者预后不良， 那些先前存在肺部疾病的患者和先前健康的个体。流感大流行的可能性 病毒的发现提高了了解疾病发病机理的重要性。此外，次级细菌 金黄色葡萄球菌肺炎的患病率正在增加，而抗生素耐药性继续存在， 传播。本申请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。期间 在上一个资助期内，我们的实验室发现了细菌诱导的17型免疫抑制 作为一种重要的易感机制。我们已在 在这种情况下，阐明异常宿主防御途径的领域。在此更新应用程序中，我们将建立 基于我们正在进行的工作，从最初的重点中衍生出三个非常新颖的目标。我们假设S. 金黄色葡萄球菌诱导的17型先天免疫激活受流感诱导的STAT 2负调控 信号传导和Asc炎性体。此外，我们建议外源性抗菌肽（AMP）治疗 提出了一种新的治疗策略，在流感，细菌的双重感染。在目标1中，我们将确定 STAT 2信号传导损害抗细菌宿主对S.流感期间的金黄色葡萄球菌 超级感染目的2将集中于Asc炎性小体敲除小鼠的机制， 防止继发性S加重。金黄色葡萄球菌感染。在目标3中，我们将研究 AMP的生产和评估外源性AMP的治疗潜力，在流感，S。金黄色超 感染拟议的研究将进一步了解流感如何损害随后的免疫力 对于S.金黄色葡萄球菌（目的1），如何免疫反应，金黄色葡萄球菌在肺中启动（目的2），并测试 用于控制流感后继发性细菌性肺炎的新治疗方法（目的3）。我们 最重要的目标是了解流感易感性的关键机制，S。金黄色超 感染并在疾病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.