Role of Neutrophils During Toxoplasmosis

描述(申请人提供)：这项赠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，以及无效免疫如何导致疾病的发病。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上严重疾病或死亡。弓形虫诱导强大的1型细胞因子反应，这是抵抗感染所必需的。这项建议侧重于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)的一个特点是能够在感染灶快速大量积聚。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过程中免疫反应点火中的重要免疫调节作用，本提案的总体目标是从分子和细胞细节上了解中性粒细胞是如何发挥这一免疫调节功能的。这项建议的目的之一是描述PMN在树突状细胞的招募和激活中所起的作用。这将通过检测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实现。第二个目标是确定PMN中存在的细胞因子和趋化因子在多大程度上是预先形成的池，而不是由于寄生虫刺激而新合成的，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)是最近出现的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在中性粒细胞上的表达模式，并与树突状细胞进行比较。还将确定TLR在弓形虫抗原刺激和细胞内感染期间的表达变化。这些研究有望阐明弓形虫的免疫反应是如何启动的，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，有望导致更有效地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.