Influence of Macrophage NF-kB Activation on the Outcome of Pneumococcal Pneumonia

描述(申请人提供)：肺炎球菌肺炎是美国感染相关死亡的主要原因。在肺炎球菌肺炎期间，会发生强烈的炎症反应，包括局部细胞因子的产生、中性粒细胞的迁移和血浆成分的外溢。感染性肺炎的病理生理转归在很大程度上是基于细菌诱导的细胞因子信号，该信号通过核因子-β途径调节促炎基因的表达。我们实验室以前的研究表明，在肺部对细菌刺激的反应中，NF-βrelA对于介导中性粒细胞募集的趋化因子和黏附分子的转录是必不可少的。此外，阻断RELA被证明严重影响了细菌从肺部的清除。在了解特定细胞类型在肺炎中的作用方面，我们的实验室还表明，肺泡巨噬细胞是最早在肺部遇到病原体的白细胞，它会分泌依赖于核因子-β的细胞因子，这些细胞因子对肺防御至关重要。肺炎球菌在大多数儿童出生后的头几年会在鼻咽部定植。然而，肺炎球菌鼻咽定植可以进展到下呼吸道，在那里可能会引发危及生命的疾病。目前，肺炎球菌有90多种不同的血清型，人们对疾病进展的了解大多集中在血清型上。虽然血清型是一个重要的毒力因素，但它本身确实解释了为什么肺炎球菌病在一些人中进展为侵袭性疾病，而在另一些人中则不是。即使在给定的血清型中，不同的分离物也有不同的致病能力，这一事实使这一观察结果进一步复杂化；这表明这些差异是由于不依赖于衣壳的毒力因素造成的。阐明其他毒力决定因素将极大地增强我们对患者所见疾病发病机制范围的了解。我们建议揭示肺炎球菌感染时引导肺部天然免疫的分子机制(如巨噬细胞核因子B激活和细胞因子表达)，并检查肺炎球菌对这一反应的颠覆是否是一个关键的毒力决定因素。我们推测，不同的肺炎球菌在激活巨噬细胞核因子？B的能力上有所不同，而那些破坏巨噬细胞激活的菌株更有能力导致严重肺炎。从这些研究中获得的生物学见解将有助于我们更好地了解宿主对肺炎球菌的反应是否是感染的关键决定因素，以便识别易感个体，特别是强毒肺炎球菌。 公共卫生相关性：肺炎球菌肺炎是全球疾病的主要原因，在美国每年导致显著的发病率和死亡率。我们的目标是更好地了解选定免疫细胞(巨噬细胞中的核因子-KB)中的特定信号通路如何决定这种细菌肺部感染的结果。这些知识将指导未来的研究 旨在识别特别敏感的个体，特别是毒力强的细菌。

DESCRIPTION (provided by applicant): Pneumococcal pneumonia is a leading cause of infection-related deaths in the United States. During pneumococcal pneumonia, an intense inflammatory reaction occurs that involves local cytokine production, neutrophil emigration, and the extravasation of plasma constituents. The pathophysiological outcome of infectious pneumonia is largely based on bacteria-induced cytokine signaling that regulates the expression of proinflammatory genes through the NF-?B pathway. Previous studies from our lab have shown that in response to bacterial stimuli in the lungs, NF-?B RelA is essential for the transcription of chemokines and adhesion molecules that mediate neutrophil recruitment. Furthermore, interrupting RelA was shown to seriously compromise bacterial clearance from the lungs. In terms of understanding the role of specific cell types in the lung during pneumonia, our lab has also shown that alveolar macrophages, which are the first leukocytes to encounter pathogens in the lung, secrete cytokines that are dependent upon NF-?B and critical to lung defense. Pneumococcus colonizes the nasopharynx of most children during the first few years of life. However, pneumococcal nasopharyngeal colonization can progress into the lower respiratory tract, where life- threatening disease can be initiated. Currently, there are over 90 different serotypes of pneumococcus, and much of what is known about disease progression is often serotype focused. Although a prominent virulence factor, serotype alone does explain why pneumococcal disease in some individuals progresses to invasive disease but not in others. This observation is further complicated by the fact that even within a given serotype different isolates have varying abilities to cause disease; which would suggest that these differences were due to virulence factors independent of the capsule. Elucidation of other virulence determinants would greatly enhance our understanding of the range of disease pathogenesis seen in patients. We propose to uncover the molecular mechanisms (such as macrophage NF-?B activation and cytokine expression) that direct innate immunity in the lungs during pneumococcal infection and examine whether pneumococcal subversion of this response is a critical virulence determinant. We hypothesize that different pneumococcal isolates vary in their ability to activate macrophage NF-?B and those that subvert macrophage activation are more capable of causing severe pneumonia. The biological insights gained from these studies will help us better understand whether host responses to pneumococcus are critical determinants of infection in order to identify susceptible individuals and particularly virulent pneumococci. PUBLIC HEALTH RELEVANCE: Pneumococcal pneumonia is a major cause of disease worldwide and causes significant annual morbidity and mortality in the U.S. Our goal is to better understand how a specific signaling pathway in select immune cells (NF-KB in macrophages) dictates the outcome of lung infection with this bacteria. This knowledge will guide future studies aiming to identify especially susceptible individuals and especially virulent bacteria.