Cytokine-stimulated systemic defenses during pneumococcal pneumonia

描述(申请人提供)：肺炎链球菌(肺炎球菌)是社区获得性肺炎最常见的原因。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，从无症状的上呼吸道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时相反应，并检查肺炎球菌对这种反应的颠覆是否是肺部感染过程中的一个关键毒力决定因素。肺炎时肝脏的急性期反应由细胞因子触发，肝脏的激活依赖于IL-6(触发STAT3)和肿瘤坏死因子和IL-1(触发核因子-β)。我们推测，肺炎期间这些细胞因子的表达是由常驻肺髓系细胞中的NF-βRelA驱动的，然后这些细胞因子激活肝细胞中的STAT3和NF-β，介导急性期蛋白的表达，这对于防止感染和炎性损伤从肺部扩散到其他器官和组织是必不可少的。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从感染肺扩散的中心假设，我们建议追求以下特定目标：1)利用髓系细胞和常驻肺白细胞中relA突变选择性地抑制细胞因子表达的小鼠，验证肺内滞留巨噬细胞和树突状细胞在肺炎期间启动肝脏急性期反应的假说。2)利用肝细胞中选择性地联合靶向STAT3和RERA抑制肝脏急性期反应的小鼠，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)的扩散的假设。3)在体外筛选和体内感染模型中，使用无症状携带者或细菌性肺炎患者的临床分离株，验证颠覆肝脏急性时相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。创新包括将被测试的新概念，以及在选定细胞中缺乏relA和/或STAT3的小鼠，以及肺炎球菌临床分离株的体外筛选试验。拟议的研究将对填补知识空白(阐明肺炎期间急性时相反应的调节和功能)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敏感的患者，特别是强毒肺炎球菌。 与公共卫生相关：肺炎链球菌(肺炎球菌)感染是肺炎的主要原因，肺炎球菌从肺部传播也会导致危及生命的血液和脑部感染。拟议的研究将测试肝脏的激活是否以及如何防止感染和疾病从肺部传播到其他器官。这一新知识将指导进一步的研究，旨在识别特别敏感的人和特别毒力的细菌，以便更好地预防和治疗肺炎球菌感染。

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-?B). We postulate that expression of these cytokines during pneumonia is driven by NF-?B RelA in resident lung myeloid cells, and these cytokines then activate both STAT3 and NF-?B 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. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae (pneumococcus) infection is the leading cause of pneumonia, and the spreading of pneumococcus from the lungs also causes bloodstream and brain infections which are life-threatening. The proposed studies will test whether and how activation of the liver prevents the spread of infection and disease from the lung to other organs. This new knowledge will guide further studies aiming to identify people who are especially susceptible and bacteria that are especially virulent, in order to better prevent and treat pneumococcal infections.