Role of Neutrophils During Toxoplasmosis

描述（由申请人提供）：本资助申请的长期目标是了解成功控制机会性原生动物刚地弓形虫感染所需的免疫反应机制，以及无效免疫如何导致疾病发病。这种寄生虫是一种主要的艾滋病病原体，可引起先天性感染婴儿的严重疾病或死亡。弓形虫诱导有效的1型细胞因子反应，这是抵抗感染所必需的。本研究的重点是中性粒细胞在小鼠对弓形虫感染的先天免疫反应中的作用。多形核白细胞（PMN）的一个显著特征是它们在感染病灶迅速大量积累的能力。我们和其他人最近的工作揭示了中性粒细胞在微生物感染期间免疫反应点燃中的重要免疫调节作用，本提案的总体目标是在分子和细胞细节上了解中性粒细胞如何发挥这种免疫调节功能。这个建议的一个目的是表征PMN在树突状细胞的招募和激活中所起的作用。这将通过检查寄生虫刺激的中性粒细胞如何在体外和体内影响树突状细胞的活性来完成。第二个目标是确定细胞因子和趋化因子在PMN中作为预先形成的池与作为寄生虫刺激的新合成的池中存在的程度，并确定外源细胞因子如何控制每个细胞因子池的释放。本研究的另一个目标是启动生化研究，以确定在弓形虫刺激过程中MAPK和NFkappaB信号通路在控制中性粒细胞细胞因子产生中的作用。最后，toll样受体（TLR）最近成为一类主要的模式识别受体，参与微生物病原体的先天免疫检测。我们将研究TLR在中性粒细胞和树突状细胞上的表达模式。还将确定TLR表达在弓形虫抗原刺激和细胞内感染期间如何变化。这些研究有望阐明弓形虫免疫应答是如何启动的，以及中性粒细胞在这一过程中的作用。了解免疫是如何触发的，有望带来更有效的方法来控制弓形虫和其他微生物病原体的感染。

DESCRIPTION (provided by the applicant): The long-term objective of this grant application is to understand the immune response mechanisms that are required to successfully control infection with the opportunistic protozoan Toxoplasma gondii, and how ineffective immunity contributes to pathogenesis of disease. The parasite is a major AIDS pathogen and can cause severe disease or death in congenitally infected infants. Toxoplasma induces potent Type 1 cytokine responses that are required in resistance to infection. This proposal focuses on the role of neutrophils in the mouse innate immune response to T. gondii infection. A hallmark characteristic of polymorphonuclear leukocytes (PMN) is their ability to rapidly accumulate in large numbers at foci of infection. Recent work by us and others has revealed an important immunoregulatory role for neutrophils in immune response ignition during microbial infection, and the overall goal of this proposal is to understand in molecular and cellular detail how neutrophils exert this immunoregulatory function. An aim of this proposal is to characterize the role that PMN play in recruitment and activation of dendritic cells. This will be accomplished by examining how parasite-stimulated neutrophils influence dendritic cell activity both in vitro and in vivo. A second aim is to determine the extent to which cytokines and chemokines are present within PMN as preformed pools versus newly synthesized as a result of parasite stimulation, and to determine how exogenous cytokines control release of each cytokine pool. Another goal of this study is to initiate biochemical studies to define the role of MAPK and NFkappaB signaling pathways in control of neutrophil cytokine production during T. gondii stimulation. Finally, Toll-like receptors (TLR) have recently emerged as a major class of pattern recognition receptors involved in innate immune detection of microbial pathogens. The expression pattern of TLR on neutrophils and compared to dendritic cells will be examined. It will also be determined how TLR expression changes during stimulation with T. gondii antigen and during intracellular infection. These studies are expected to clarify how the immune response to Toxoplasma is initiated, and the function of neutrophils in this process. Understanding how immunity is triggered can be expected to lead to more effective means of controlling infection with Toxoplasma and other microbial pathogens.