Role of type III interferons in Staphylococcus aureus respiratory tract infection

总结 金黄色葡萄球菌是人类呼吸道和流感的主要病原体 合并感染是随后感染的主要诱发因素。提高抗生素 耐药性是一个主要问题，在缺乏对保护性疫苗的了解的情况下， 感染中的细菌和宿主过程将确定新的治疗目标。主机 炎症过程参与S.金黄色葡萄球菌感染的肺部不好 理解，但我们已经确定了III型干扰素途径被激活后S。 金黄色葡萄球菌感染。III型干扰素信号转导有助于S.金黄色 在急性肺炎期间在鼻咽和肺部定植， 导致过度的免疫病理学。此应用程序将描绘多个 III型干扰素导致S.金黄色引起的疾病。在Aim中 1我们将研究III型干扰素对中性粒细胞功能和信号传导的影响， 在目标2中，我们将检查它们影响炎性小体的能力。在目标3中， 确定该途径的保守激活在各种临床 标本，并确定主要的细胞类型产生III型干扰素。我们亦会研究 IFN抗体中和在正常条件下清除感染中的效用， 流感合并感染，并与目前的抗菌药物一致。我们将利用我们的 最近开发的人源化感染模型，以证实我们的观察， 改进的感染模型。在这些研究结束时，我们将扩大 我们对III型干扰素如何促进S.金黄色 肺炎，并将确定治疗改善的靶向机制 宿主免疫病理学的变化。

SUMMARY Staphylococcus aureus is a major human pathogen of the respiratory tract and influenza co-infection is a major predisposing factor for subsequent infection. Increasing antibiotic resistance is a major concern and in the absence of a protective vaccine understanding the bacterial and host processes in infection will identify new treatment targets. The host inflammatory processes involved in S. aureus infection of the lung are not well understood, but we have identified the type III interferon pathway to be activated upon S. aureus infection. Type III interferon signaling contributes to the ability of S. aureus to colonize the nasopharynx as well as in the lung during acute pneumonia where they contribute to excessive immunopathology. This application will delineate the multiple mechanisms behind type III interferons contributing to S. aureus-induced disease. In Aim 1 we will investigate the influence of type III IFNs on neutrophil function and signaling and in Aim 2 we will examine their ability to influence the inflammasome. In Aim 3 we will determine how conserved activation of this pathway is across a variety of clinical specimens and identify the major cell types producing type III IFN. We will also examine the utility of IFN antibody neutralization in clearing infection under normal conditions and influenza co-infection, and in concert with current antimicrobials. We will utilize our recently developed humanized model of infection to confirm our observations in an improved model of infection. At the conclusion of these studies, we will have expanded our knowledge on how type III IFNs contribute to the pathogenesis of S. aureus pneumonia, and will have identified targetable mechanisms for therapeutic amelioration of host immunopathology due to IFN production.