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

描述（由申请人提供）：肺炎球菌性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，发生强烈的炎症反应，涉及局部细胞因子产生、中性粒细胞移出和血浆成分外渗。感染性肺炎的病理生理结果在很大程度上是基于细菌诱导的细胞因子信号传导，通过NF-κ B调节促炎基因的表达。B途径。我们实验室以前的研究表明，在肺部细菌刺激的反应，NF-？B RelA对于介导中性粒细胞募集的趋化因子和粘附分子的转录至关重要。此外，中断RelA显示严重损害肺部细菌清除。在了解肺炎期间肺中特定细胞类型的作用方面，我们的实验室还表明，肺泡巨噬细胞是肺中遇到病原体的第一个白细胞，分泌依赖于NF-？B对肺部防御至关重要。肺炎球菌在大多数儿童生命的最初几年内定植在鼻咽部。然而，肺炎球菌鼻咽定植可进展到下呼吸道，在那里可引发危及生命的疾病。目前，有超过90种不同的肺炎球菌血清型，并且大多数关于疾病进展的知识通常集中在血清型上。虽然是一个重要的毒力因子，但血清型本身确实解释了为什么肺炎球菌疾病在某些个体中发展为侵袭性疾病，而在其他个体中则不是。这一观察结果进一步复杂化，因为即使在给定的血清型内，不同的分离株也具有不同的致病能力;这表明这些差异是由于与荚膜无关的毒力因子所致。阐明其他毒力决定因素将大大提高我们对患者发病机制的理解。我们建议揭示分子机制（如巨噬细胞NF-？B激活和细胞因子表达），其在肺炎球菌感染期间指导肺中的先天免疫，并检查肺炎球菌对这种应答的颠覆是否是关键的毒力决定因素。我们推测，不同的肺炎球菌菌株在其激活巨噬细胞NF-？B和那些破坏巨噬细胞活化的更能引起严重的肺炎。从这些研究中获得的生物学见解将帮助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，以确定易感个体，特别是毒性肺炎球菌。

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.