Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

描述(申请人提供)：甲型H1N1流感是美国发病率和死亡率的主要原因。此外，正如过去两年所证明的那样，甲型流感构成了大流行爆发的重大风险。大部分严重的甲型流感肺炎病例与继发性细菌感染有关，最常见的是由金黄色葡萄球菌或肺炎链球菌引起的。由于甲氧西林耐药(MRSA)菌株的出现，金黄色葡萄球菌肺炎的发病率和严重性在全球范围内都在增加。因此，了解促进肺部细菌宿主防御的分子机制至关重要。人们对金黄色葡萄球菌感染的细胞免疫反应知之甚少。利用甲型流感感染的小鼠模型(甲型流感病毒PR/8/34)和金黄色葡萄球菌的攻击，我们小组发现甲型流感会加剧继发性细菌性肺炎。我们已经证明，其机制可能是通过I型干扰素抑制IL-23的产生和随后的TH17免疫激活来实现的。在这项提案中，我们将从三个具体目标进一步研究甲型流感和金黄色葡萄球菌混合感染模型。首先，我们将研究I型干扰素在A型流感继发性细菌感染加重中的作用。其次，我们将研究IL-23促进金黄色葡萄球菌免疫的机制。最后，我们将探讨TH17途径通过呼吸道上皮促进金黄色葡萄球菌杀灭的机制。这些研究将涉及大量TH17途径基因改变的小鼠研究，以及对小鼠和人类呼吸道上皮细胞的体外研究。本研究的目的是阐明金黄色葡萄球菌宿主防御的分子机制，并寻找能够恢复甲型流感病毒感染后TH17免疫的干预措施，并改善宿主对继发性细菌性肺炎的反应。这些数据可能直接适用于医院环境，并可能揭示新的治疗策略，将降低发病率和死亡率，并改善患者预后。

DESCRIPTION (provided by applicant): Influenza A H1N1 represents a major cause of morbidity and mortality in the United States. In addition, Influenza A poses a significant risk of pandemic outbreak as evidenced in the past two years. A large proportion of severe cases of Influenza A pneumonia are associated with secondary bacterial infection, most commonly caused by Staphylococcus aureus or Streptococcus pneumoniae. Incidence and severity of S. aureus pneumonia is increasing worldwide due to the emergence of methicillin-resistant (MRSA) strains. For these reasons, understanding the molecular mechanisms that promote bacterial host defense in the lung is of critical importance. Little is known about the cell-mediated immune response to S. aureus infection. Using a mouse model of Influenza A infection (Influenza A PR/8/34) coupled with S. aureus challenge our group has found that Influenza A exacerbates secondary bacterial pneumonia. We have shown that the mechanism is likely mediated by type I Interferon suppression of IL-23 production and subsequent TH17 immune activation. In this proposal we will further investigate the Influenza A, S. aureus co-infection model in three specific aims. First, we will examine the role of type I interferon in mediating Influenza A exacerbation of secondary bacterial infection. Second, we will examine the mechanism by which IL-23 promotes immunity against S. aureus. Finally, we will investigate the mechanism by which the TH17 pathway promotes S. aureus killing via the airway epithelium. These studies will involve numerous TH17 pathway gene altered mouse studies and in vitro studies with both mouse and human airway epithelial cells. The goal of the study is to elucidate the molecular mechanisms involved in S. aureus host defense and to identify interventions that can restore TH17 immunity following Influenza A infection and improve the host response against secondary bacterial pneumonia. These data may be directly applicable to the hospital setting and may reveal novel therapeutic strategies that would decrease morbidity and mortality, and improve patient outcome.