Regulation of Type1 Immunity to Toxoplasma

描述（由申请方提供）：弓形虫是人和动物中的主要机会寄生虫感染因子。疾病可由导致宿主组织的寄生虫溶解的弱免疫应答引起，或者可由不适当或过度旺盛的免疫应答引起。T.弓形虫和其它细胞内病原体的免疫应答是由辅助性T细胞1（Th 1）介导的，辅助性T细胞1产生促炎细胞因子IFN-γ和TNF-α。然而，当过量产生时，这些保护性细胞因子可能成为病理性的。Th 1细胞是如何自我调节的还没有得到很好的理解。我们在上一个资助期的工作揭示了Th 1应答中的一个关键负控制回路，IFN-γ诱导抗炎细胞因子IL-10，Th 1细胞本身的产生。因此，本申请将确定IL-10如何被调节和起作用以保护宿主免受自身造成的免疫损伤。我们的第一个目标是首先确定是什么信号和细胞编程Th 1细胞产生IL-10。其次，我们将研究特化的先天细胞在驱动产生IL-10的Th 1细胞分化中的作用。最后，我们将阐明负反馈回路的细胞因子和细胞成分，由此IFN-γ诱导Th 1记忆细胞中IL-10的再激活。这些研究将确定免疫系统用于同时清除微生物病原体和防止宿主组织损伤的关键机制。公共卫生相关性：寄生原虫和其他类型的细胞内病原体引起的人类疾病是全球人类死亡和发病的主要原因。疾病可能是由寄生虫造成的组织破坏或由免疫反应过度引起的。本文提出的研究将促进对Th 1应答如何提供针对寄生虫和其他病原体的保护以及预防或避免附带组织损伤的理解。从这项研究中获得的见解有望对慢性传染病的管理策略和治疗有用。

DESCRIPTION (provided by applicant): Toxoplasma gondii is a major opportunistic parasitic infectious agent in man and animals. Disease can result from a weak immune response resulting in parasite lysis of host tissue or it can ensue from an inappropriate or overly exuberant immune reaction. The major protective immune mechanism against T. gondii and other intracellular pathogens is that mediated by T helper 1 (Th1) cells, which produce pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Nevertheless, when produced in excess, these protective cytokines can become pathologic. How Th1 cells are self-regulated has not been well understood. Our work from the previous funding period has unraveled a key negative control loop in Th1 responses whereby IFN-gamma induces the production of the anti-inflammatory cytokine IL-10, Th1 cells themselves. Therefore, the current application will determine how IL-10 is regulated and functions to protect the host from self-inflicted immune-injury. Our first aim is to determine what signals and cells program the Th1 cells to produce IL-10 in the first place. Secondly, we will investigate the role of specialized innate cells in driving the differentiation of Th1 cells producing IL-10. Finally, we will elucidate the cytokine and cellular components of the negative feedback loop whereby IFN-gamma induces reactivation of IL-10 in Th1 memory cells. These studies will identify key mechanisms used by the immune system to simultaneously clear microbial pathogens but also prevent host tissue damage. PUBLIC HEALTH RELEVANCE: Human diseases caused parasitic protozoa and other types of intracellular pathogens are major causes of human mortality and morbidity globally. Disease may be caused by tissue destruction by parasites or result from an over-reaction by the immune response. The studies proposed here will advance understanding of how the Th1 response can provide protection against parasites and other pathogens but also prevent or avert collateral tissue damage. Insights obtained from this research will hopefully be useful for management strategies and treatment for chronic infectious diseases.