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，甚至导致患者预后不佳。 在以前健康的个体中。此外，继发性细菌性肺炎合并金黄色葡萄球菌 患病率增加，现在比肺炎链球菌更常见，以前 主要病原体。缺乏有效的抗病毒治疗药物和免疫调节药物，而且越来越多 抗生素耐药性，加上疫苗覆盖率和有效性较差，导致迫切需要新的 治疗靶点识别。本应用的重点是了解由流感引发的 细菌双重感染的易感性机制，是季节性和季节性死亡的主要原因 大流行爆发。在之前的资助期间，我们的实验室发现抑制了 通过先于流感作为关键易感机制的细菌诱导的17型免疫反应。 我们已经在这一领域发表了大量的文章，阐明了在这一背景下的异常宿主防御途径。在这 应用程序，我们将以我们正在进行的工作为基础，从最初的重点衍生出两个非常新颖的目标。我们 现在提供了关于III型干扰素(干扰素λ)在双重感染中的有害作用的初步数据 通过抑制单核细胞功能和模式识别受体的表达。这些数据支持 流感诱导干扰素λ直接抑制单核细胞抗菌功能的假说 SIGNR3/4，它是随后激活17型免疫和清除金黄色葡萄球菌所必需的 超级感染。在目标1中，我们将确定干扰素λ抑制单核细胞功能的机制。 流感、金黄色葡萄球菌双重感染。在目标2中，我们将定义SIGNR3/4在宿主防御S. 肺部有金黄色物质。拟议的研究将进一步加深我们对流感如何损害后续 对金黄色葡萄球菌的免疫(目标1)以及流感的免疫反应如何减弱金黄色葡萄球菌的清除 在肺中(目标2)。我们的首要目标是了解流感易感性的关键机制(S)， 在疾病的临床前模型中确定新的治疗靶点。

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 even in previously healthy individuals. Further, secondary bacterial pneumonia with Staphylococcus aureus is increasing in prevalence and is now more common than Streptococcus pneumoniae, the previously predominant pathogen. The lack of effective anti-viral therapeutics, immunomodulatory drugs, and increasing antibiotic resistance, coupled with poor vaccine coverage and efficacy, results in a dire need for novel therapeutic target identification. The focus of this application is upon understanding the influenza-induced mechanisms of susceptibility to bacterial super-infection, the leading cause of death during seasonal and pandemic outbreaks. During the previous funding periods, 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 this area, elucidating aberrant host defense pathways in this context. In this application, we will build upon our ongoing work with two highly novel Aims derived from the original focus. We now provide preliminary data implicating a detrimental role for type III interferon (IFNλ) in super-infection through inhibiting monocyte function and pattern recognition receptor expression. These data support the hypothesis that influenza induced IFNλ directly inhibits monocyte antibacterial function via suppression of SIGNR3/4, which is required for subsequent activation of Type 17 immunity and S. aureus clearance during super-infection. In Aim 1, we will determine the mechanism by which IFNλ inhibits monocyte function during influenza, S. aureus super-infection. In Aim 2, we will define the role of SIGNR3/4 in host defense against S. aureus in the lung. The proposed studies will further our understanding of how influenza impairs subsequent immunity against S. aureus (Aim 1) and how the immune response to influenza attenuate S. aureus clearance in the lung (Aim 2). Our overriding goal is to understand the critical mechanism(s) of susceptibility to influenza, S. aureus super-infection and identify novel treatment targets in a pre-clinical model of disease.