New insights into early T cell protection during acute toxoplasmosis

项目摘要/摘要 弓形虫是一种机会性原生动物病原体，广泛存在于人类、家畜、 牲畜和野生动物。这种寄生虫以其能够触发强烈的炎症免疫反应而闻名。 这在保护宿主免受感染方面是有效的，但尽管如此，有时还是会导致严重的 免疫介导的组织损伤。这项建议的长期目标是了解 防止感染弓形虫和其他微生物的先天和后天免疫反应 病原体。我们在小鼠感染模型中的初步数据揭示了早期T细胞免疫的某些方面 尽管过去几十年的研究表明，弓形虫以前并没有被发现。感染了 正常复制缺陷的弓形虫株cps1-1可诱导早期保护性的CD4+和CD8+T细胞 既不需要IL-12也不需要Toll样受体适配器MyD88的反应，只部分涉及干扰素-g， 而这对于防止这种寄生虫菌株以致命的方式表现是至关重要的。该项目的目标是 是为了了解这些T细胞在保护弓形虫方面的功能。中心假说 推动这项研究的是，感染引发的T细胞显示出新的激活和抗病毒机制 微生物功能。三个具体目标将对这一假设进行评估。目标1：确定cps1-1- 诱导T淋巴细胞在常规或非常规抗原特异性、MHC限制性的情况下发挥作用 举止。我们将采用采用转移的方法来确定寄生虫诱导的T细胞是否在经典的 MHC I类和MHC II类限制了同源抗原的表达。目标2：确定 Cps1-1诱导的CD_4~+和CD_8~+T淋巴细胞转录谱和激活表型。RNA序列 将用于标识保护所需的单元格显示的基础属性。目标3：确定 控制cps1-1感染的效应机制。我们将确定两种T细胞介质CD154和CD154是如何 穿孔素，与干扰素-g共同作用，采用过继转移和基因敲除的方法控制感染 老鼠。这项研究的重要性在于，我们将揭示以前未被认识到的免疫方面 致弓形虫。这可能会影响我们对感染的理解，并最终影响我们治疗感染的能力 弓形虫和其他微生物病原体。

Project Summary/Abstract Toxoplasma gondii is an opportunistic protozoan pathogen widespread in humans, domestic animals, livestock and wildlife. The parasite is known for its ability to trigger a strong inflammatory immune response that is effective in protecting the host from infection, but that can nonetheless sometimes cause severe immune-mediated tissue damage. The long-term objective of this proposal is to understand the basis of innate and acquired immune responses that protect against infection with T. gondii and other microbial pathogens. Our preliminary data in mouse models of infection reveal aspects of early T cell immunity to Toxoplasma that have not previously been recognized, despite many decades of past research. Infection with cps1-1, a normally replication-defective Toxoplasma strain, elicits an early protective CD4+ and CD8+ T cell response that requires neither IL-12 nor Toll-like receptor adaptor MyD88, that only partially involves IFN-g, and that is essential to prevent this parasite strain from behaving in a virulent manner. The goal of the project is to understand the function of these T cells in protection against Toxoplasma. The central hypothesis driving the research is that the T cells elicited by infection display novel mechanisms of activation and anti- microbial function. Three specific aims will evaluate the hypothesis. Aim 1: Determine whether cps1-1- induced T lymphocytes function in a conventional or nonconventional antigen-specific, MHC-restricted manner. We will employ adoptive transfer approaches to determine if parasite-induced T cells act in a classical MHC class I and MHC class II restricted manner involving cognate antigen. Aim 2: Determine the transcriptomic profile and activation phenotype of cps1-1-induced CD4+ and CD8+ T lymphocytes. RNA-seq will be used to identify the underlying properties displayed by the cells necessary for protection. Aim 3: Identify effector mechanisms controlling cps1-1 infection. We will determine how two T cell mediators, CD154 and perforin, act with IFN-g to control infection employing an adoptive transfer approach along with gene knockout mice. The importance of this research is that we stand to reveal previously unrecognized aspects of immunity to Toxoplasma. This can be expected to impact our understanding and ultimately ability to treat infection with Toxoplasma and other microbial pathogens.