Role of Macrophage Migration Inhibitory Factor (MIF) in Pneumococcal Pathogenesis

描述(申请人提供)：尽管使用了抗生素和疫苗，肺炎链球菌(肺炎球菌)仍然是社区获得性肺炎和死亡的主要原因。肺炎球菌在人群中是作为上呼吸道(URT)粘膜表面的共生定殖者存在的，这是下呼吸道(LRT)感染的先兆。到目前为止的研究表明，肺炎球菌与宿主免疫系统有各种相互作用，这是由细菌和宿主因素以及界面的解剖位置决定的。导致细菌从其在城市轨道交通粘膜表面的共生生态位中清除的宿主因素尚未很好地确定。此外，在LRT侵袭性肺炎球菌感染的情况下，通常是宿主炎症反应的活跃导致了发病率和死亡率。我的初步数据表明，巨噬细胞移动抑制因子(MIF)在肺炎球菌感染中发挥着重要作用，巨噬细胞移动抑制因子是一种细胞因子，也是先天性免疫反应的上游介质。在一个有机体的鼻腔定植模型中，我已经证明了MIF缺陷小鼠在清除URT肺炎球菌定植的能力方面存在显著缺陷。相反，MIF似乎在小鼠肺炎球菌LRT感染中起着有害的作用。我已经证明，在这个模型中，MIF的存在与局部细胞因子的产生增加和中性粒细胞流入有关，从而导致肺组织破坏、细菌传播和更高的死亡率。我对K08建议的假设是，MIF在肺炎球菌的发病机制中具有双重作用--它是巨噬细胞介导的URT定植清除所必需的，但也促进了LRT中侵袭性感染的炎性组织损伤。在目标1中，我将通过检测MIF在巨噬细胞募集、激活和功能中的作用来研究MIF促进肺炎球菌在城市轨道交通中定植清除的机制。在第二个目标中，我将探讨MIF在LRT中致病性中性粒细胞募集和激活中的作用。在耶鲁，我开始接受研究方法和对传染病病原体的先天免疫力方面的培训，当时我是博士生，也是理查德·布卡拉博士实验室的传染病研究员，他是我这项提议的共同导师。现在，作为宾夕法尼亚大学的博士后研究员，在杰弗里·韦瑟博士的指导下，我计划研究免疫系统与肺炎球菌从定植到疾病的相互作用机制。在这项提案的整个过程中，我已经组建了一个指导委员会和一个培训计划，这将作为我作为一名独立调查员的职业生涯的基础，研究先天免疫在宿主与病原体相互作用中的作用。肺炎球菌病仍然是各年龄段发病率和死亡率的主要原因。了解免疫系统与细菌之间的相互作用将使我们能够理解肺炎球菌如何作为鼻黏膜的定殖者存在，但会在肺部引起破坏性的侵袭性疾病。我在宿主细胞因子、巨噬细胞移动抑制因子在病原体定植和疾病中的作用方面的工作可能会导致新的疫苗接种策略、免疫调节疗法，或者识别出严重肺炎球菌疾病的最高风险患者。

DESCRIPTION (provided by applicant): Despite the use of antibiotics and vaccines, Streptococcus pneumoniae (pneumococcus) remains a leading cause of community acquired pneumonia and mortality. Pneumococcal strains are maintained in the population as commensal colonizers of the mucosal surfaces of the upper respiratory tract (URT), which is a precursor to infection of the lower respiratory tract (LRT). Research to date indicates that the pneumococcus has a variety of interactions with the host immune system that are dictated by bacterial as well as host factors, and the anatomical location of the interface. Host factors that lead to the clearance of the bacterium from its commensal niche on the mucosal surface of URT are not well defined. Moreover, it is often the exuberance of the host inflammatory response that leads to morbidity and mortality in the case of invasive pneumococcal infection in the LRT. My preliminary data demonstrate an important role for macrophage migration inhibitory factor (MIF), a cytokine and upstream mediator of the innate immune response, in pneumococcal infection. In a model of nasal colonization with the organism, I have shown that MIF-deficient mice have a prominent defect in the ability to clear URT pneumococcal colonization. In contrast, MIF seems to play a detrimental role in murine LRT infection with pneumococcus. I have demonstrated that presence of MIF in this model is associated with increased local cytokine production and neutrophil influx, resulting in lung tissue destruction, bacterial dissemination, and greater mortality. My hypothesis for this K08 proposal is that MIF has a dual role in pneumococcal pathogenesis - it is necessary for macrophage mediated clearance of URT colonization, but also promotes inflammatory tissue damage in response to invasive infection in the LRT. In Aim#1, I will investigate the mechanism by which MIF promotes clearance of pneumococcal colonization in the URT by examining the role of MIF in macrophage recruitment, activation, and function. In Aim#2, I will explore the contribution of MIF to pathogenic neutrophil recruitment and activation in the LRT. At Yale, I began my training in research methodology and innate immunity to infectious pathogens as a PhD candidate as well as an infectious disease fellow in the laboratory of Dr. Richard Bucala, who serves as my co-mentor for this proposal. Now as a post-doctoral researcher at the University of Pennsylvania, with Dr. Jeffrey Weiser as my primary mentor, I plan to examine the mechanisms by which the immune system interacts with pneumococcus from colonization to disease. I have assembled a mentorship committee as well as a program of training throughout the course of this proposal that will serve as the basis for my career as an independent investigator examining the role of innate immunity in host-pathogen interactions. Pneumococcal disease remains a major cause of morbidity and mortality across the spectrum of age. Understanding the interaction between the immune system with the bacterium will allow us to appreciate how pneumococcus exists as a colonizer in the nasal mucosa but causes destructive invasive disease in the lungs. My work on the role of the host cytokine, macrophage migration inhibitory factor in both colonization and disease with the pathogen may lead to novel vaccination strategies, immune modulating therapies, or identification of patients at greatest risk for severe pneumococcal disease.