Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

描述（由申请方提供）：甲型H1N1流感是美国发病率和死亡率的主要原因。此外，甲型流感构成爆发大流行的重大风险，这在过去两年已得到证实。大部分甲型流感肺炎重症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。S.由于耐甲氧西林（MRSA）菌株的出现，金黄色葡萄球菌性肺炎在世界范围内不断增加。出于这些原因，了解促进肺部细菌宿主防御的分子机制至关重要。目前对S.金黄色葡萄球菌感染。使用与S.金黄色葡萄球菌的挑战，我们的小组已经发现，甲型流感加剧继发性细菌性肺炎。我们已经表明，该机制可能是由I型干扰素抑制IL-23的产生和随后的TH 17免疫激活介导的。在这份提案中，我们将进一步调查甲型流感，S。金黄色葡萄球菌共感染模型在三个特定的目标。首先，我们将研究I型干扰素在介导甲型流感继发性细菌感染恶化中的作用。其次，我们将研究IL-23促进抗S.金黄色。最后，我们将研究TH 17通路促进S.通过气道上皮杀死金黄色葡萄球菌。这些研究将涉及许多TH 17通路基因改变的小鼠研究和小鼠和人气道上皮细胞的体外研究。本研究的目的是阐明S.金黄色葡萄球菌宿主防御，并确定可以在甲型流感感染后恢复TH 17免疫力并改善宿主对继发性细菌性肺炎的反应的干预措施。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，并改善患者的结果。

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.