Role of Neutrophils During Toxoplasmosis

描述（由申请人提供）：本拨款申请的长期目标是了解成功控制机会性原生动物弓形虫感染所需的免疫反应机制，以及无效的免疫如何导致疾病的发病机制。这种寄生虫是艾滋病的主要病原体，可导致先天感染的婴儿患严重疾病或死亡。弓形虫可诱导抵抗感染所需的有效 1 型细胞因子反应。该提案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) 的一个标志特征是它们能够在感染灶处快速大量积累。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火中的重要免疫调节作用，该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。该提案的目的是描述 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影响体外和体内的树突状细胞活性来实现。第二个目的是确定 PMN 中预先形成的细胞因子和趋化因子与寄生虫刺激新合成的细胞因子和趋化因子的存在程度，并确定外源细胞因子如何控制每个细胞因子库的释放。本研究的另一个目标是启动生化研究，以确定 MAPK 和 NFkappaB 信号通路在弓形虫刺激过程中控制中性粒细胞细胞因子产生的作用。最后，Toll 样受体 (TLR) 最近作为一类主要的模式识别受体出现，参与微生物病原体的先天免疫检测。将检查中性粒细胞上 TLR 的表达模式并与树突状细胞进行比较。还将确定 TLR 表达在弓形虫抗原刺激期间和细胞内感染期间如何变化。这些研究有望阐明对弓形虫的免疫反应是如何启动的，以及中性粒细胞在此过程中的功能。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.