Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF

描述(由申请人提供)：无法获得对疟原虫的完全保护性免疫是疟疾控制的主要障碍。在模型系统中，高水平的炎性细胞因子可以抑制记忆T细胞的发育。值得注意的是，所有的疟原虫物种都被发现编码上游炎症细胞因子-巨噬细胞移动抑制因子(MIF)的同源基因。疟原虫MIF(PMIF)在感染过程中上调炎症反应，导致增强激活诱导的T细胞凋亡，并减少抗原经历的CD4T细胞成为记忆细胞。这一发现表明，疟原虫主动干扰疟疾特异性记忆CD4T细胞的产生，从而使寄生虫得以持久和传播。为了更好地了解疟疾的无效免疫，并为更好的疫苗提供基础，我们将从以下三个具体目标确定PMIF在抗疟疾免疫反应中的具体作用：目的1.确定疟原虫编码的MIF(PMIF)在免疫反应的促炎激活的分子基础。我们假设PMIF通过激活宿主MIF受体来增加炎症反应。我们将定义PMIF与宿主MIF共享的和独特的信号特性，并研究保守的N-末端区域的作用，它介导与MIF受体的结合。我们将研究PMIF在Toll样受体和NOD样受体激活通路上的作用，并将在感染了缺乏MIF基因的P.berghei Anka株的小鼠中验证我们的观察结果。目的：明确PMIF抑制抗疟疾获得性免疫反应的细胞和分子基础。我们假设，在疟疾感染期间，强烈的促炎环境有利于产生终末效应的CD4T细胞，但代价是保护性的、记忆前体的CD4T细胞。我们将阐明导致这种反应的细胞因子和信号通路，研究T滤泡辅助细胞(TFH)的作用及其为B细胞和T细胞提供帮助的能力，并分析T细胞的耗竭。目的3.评价PMIF中和治疗疟疾的潜力。我们将探讨PMIF中和对小鼠血液期和子孢子感染模型的影响。我们的方法将包括通过一种新的自我放大的RNA疫苗与PMIF免疫，以及基于我们发现的一种选择性的PMIF小分子抑制剂的药理学策略。这些研究将深入了解疟原虫如何引导宿主炎症反应干扰保护性免疫，并为治疗性免疫调节和疫苗开发提出新的策略。本工作的结论可推广到其他寄生虫病原体，如利什曼原虫、钩口线虫和布鲁氏菌，它们都产生自己的同源MIF蛋白。

DESCRIPTION (provided by applicant): The inability to acquire fully protective immunity against Plasmodium is a chief obstacle to malaria control. High levels of inflammatory cytokines can inhibit memory T cell development in model systems. Notably, all Plasmodia species have been found to encode an ortholog of the upstream inflammatory cytokine, macrophage migration inhibitory factor (MIF). Plasmodium MIF (PMIF) upregulates inflammatory responses during infection, leading to enhanced activation-induced T cell apoptosis and fewer antigen- experienced CD4 T cells that become memory cells. This finding suggests that Plasmodia actively interfere with the generation of malaria-specific memory CD4 T cells to enable parasite persistence and transmission. To better understand ineffective immunity to malaria and to provide a foundation for better vaccines, we will determine the specific role of PMIF in the anti-malarial immune response in three Specific Aims, as follow: Aim 1. Define the Molecular Basis for the Pro-inflammatory Activation of the Immune Response by Plasmodium-encoded MIF (PMIF). We hypothesize that PMIF increases inflammatory responses by activating the host MIF receptor. We will define shared and unique signaling properties of PMIF versus host MIF and examine the role of the conserved N-terminal region, which mediates binding to the MIF receptor. We will investigate the action of PMIF on Toll-like and NOD-like receptor activation pathways, and we will validate our observations in mice infected with a P. berghei ANKA strain lacking its mif gene. Aim 2. Define the Cellular and Molecular Basis for the Suppression of the Anti-malarial Adaptive Immune Response by PMIF. We hypothesize that a strong pro-inflammatory environment during malaria infection favors the generation of terminal effector CD4 T cells at the expense of protective, memory precursor CD4 T cells. We will elucidate the cytokine and signaling pathways responsible for this response, examine the role of T follicular helper cells (TFH) and their ability to provide help to B and to T cells, and analyze T cell exhaustion. Aim 3. Evaluate the Therapeutic Potential of PMIF Neutralization in Malaria. We will explore the impact of neutralization of PMIF in mouse models of blood-stage and sporozoite infection. Our approach will include immunization with PMIF by a novel self-amplifying RNA vaccine and a pharmacologic strategy based on our discovery of a selective, small molecule inhibitor of PMIF. These studies will provide insight into how Plasmodia direct the host inflammatory response to interfere with protective immunity and suggest new strategies for therapeutic immunomodulation and vaccine development. Conclusions from this work may be generalized to other parasite pathogens, such as Leishmania, Ancyclostoma, and Brugia, which produce their own closely homologous MIF proteins.