Cytokine-stimulated systemic defenses during pneumococcal pneumonia

描述（由申请人提供）：肺炎链球菌（肺炎球菌）是社区获得性肺炎的最常见原因。这种病原体与人类的相互作用是复杂的，肺炎球菌引起一系列疾病，从上呼吸道无症状定植到多器官感染和死亡。我们建议阐明肺炎球菌在肺部引发的肝脏急性期反应，并检查肺炎球菌对这种反应的破坏是否是肺部感染期间的关键毒力决定因素。肺炎期间肝脏急性期反应由细胞因子触发，肝脏激活依赖于IL-6（触发STAT3）和TNF和IL-1（触发NF-κB）。我们假设这些细胞因子在肺炎期间的表达是由驻留的肺髓细胞中的NF-κB RelA驱动的，然后这些细胞因子激活肝细胞中的STAT3和NF-κB来介导急性期蛋白表达，这对于防止感染和炎症损伤从肺部扩散到其他器官和组织至关重要。为了验证肝脏急性期反应作为血管屏障以防止感染和损伤传播的中心假设，我们提出以下具体目标：1)利用骨髓细胞和常驻肺白细胞中RelA突变选择性抑制细胞因子表达的小鼠，验证肺炎期间肺常驻巨噬细胞和树突状细胞启动肝脏急性期反应的假设。2)使用肝细胞选择性靶向STAT3和RelA抑制肝急性期反应的小鼠，验证肝脏急性期反应限制肺炎期间感染（菌血症）和损伤（ARDS和多器官衰竭）的传播的假设。3)在体外筛选和体内感染模型中，使用从无症状携带或菌源性肺炎的人类患者中分离的临床分离株，验证颠覆肝脏急性期反应的肺炎球菌在人类患者和小鼠模型中更具侵袭性的假设。创新包括有待测试的新概念，以及在选定细胞中缺乏RelA和/或STAT3的小鼠，以及临床分离肺炎球菌的体外筛选试验。所提出的研究将对填补知识空白（阐明肺炎急性期反应的调节和功能）具有重要意义，并将指导进一步的研究，旨在区分和治疗特别易感患者和特别毒力肺炎球菌。

DESCRIPTION (provided by applicant): Streptococcus pneumoniae (pneumococcus) is the most common cause of community-acquired pneumonia. Interactions of this pathogen with humans are complex, with pneumococcus causing a spectrum of disease ranging from asymptomatic colonization of upper airways to multi-organ infection and death. We propose to elucidate the hepatic acute phase response triggered by pneumococci in the lungs, and to examine whether pneumococcal subversion of this response is a critical virulence determinant during lung infection. The hepatic acute phase response is triggered by cytokines during pneumonia, with liver activation dependent on IL-6 (triggering STAT3) and on TNF and IL-1 (triggering NF-κB). We postulate that expression of these cytokines during pneumonia is driven by NF-κB RelA in resident lung myeloid cells, and these cytokines then activate both STAT3 and NF-κB in hepatocytes to mediate acute phase protein expression essential to preventing the spread of infection and inflammatory injury from the lungs to other organs and tissues. To test the central hypothesis that the hepatic acute phase response functions as a vascular shield to prevent dissemination of infection and injury from the infected lung, we propose to pursue the following specific aims: 1) Test the hypothesis that lung resident macrophages and dendritic cells initiate the hepatic acute phase response during pneumonia, using mice in which cytokine expression is inhibited by RelA mutation selectively in myeloid cells and in resident lung leukocytes. 2) Test the hypothesis that the hepatic acute phase response limits both dissemination of infection (bacteremia) and dissemination of injury (ARDS and multi-organ failure) during pneumonia, using mice in which the hepatic acute phase response is inhibited by combined targeting of both STAT3 and RelA selectively in hepatocytes. 3) Test the hypothesis that pneumococci subverting the hepatic acute phase response are more invasive in human patients and mouse models, using clinical isolates from human patients with asymptomatic carriage or bacteremic pneumonia in in vitro screens and in vivo models of infection. Innovations include the novel concepts to be tested, as well as the mice deficient in RelA and/or STAT3 in select cells and the in vitro screening assays of clinical isolates of pneumococcus. The proposed studies will have significance for filling knowledge gaps (elucidating the regulation and function of the acute phase response during pneumonia) and will guide further studies aiming to differentiate and treat particularly susceptible patients and especially virulent pneumococci.