Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF

项目摘要/摘要 无法获得对疟疾的完全保护性免疫是疟疾的主要障碍。 控制力。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性病毒的同源基因 细胞因子，巨噬细胞移动抑制因子。疟原虫MIF(PMIF)上调炎症反应 感染过程中的反应，导致增强激活诱导的T细胞凋亡和较少的抗原- 经历过的CD4T细胞变成了记忆细胞。这一发现表明，疟原虫主动干扰 通过产生疟疾特异性记忆CD4T细胞来实现寄生虫的持久性和 变速箱。 为了更好地了解对疟疾的无效免疫，并为更好的疫苗提供基础， 我们将在三个特定目标中确定PMIF在抗疟疾免疫反应中的具体作用，如 目标1.确定免疫促炎激活的分子基础 疟原虫编码的MIF(PMIF)的应答。我们假设PMIF增加炎症性 通过激活宿主MIF受体进行反应。我们将定义共享的和唯一的信令属性 PMIF与宿主MIF的比较，并研究保守的N-末端区域的作用，该区域介导与 MIF受体。我们将研究PMIF在Toll样受体和Nod样受体激活中的作用 途径，我们将在感染了缺乏其基因的伯氏杆菌安卡株的小鼠身上验证我们的观察结果。 MIF基因。目的2.确定抑制疟疾的细胞和分子基础 PMIF的获得性免疫反应。我们假设一个强烈的促炎环境 在疟疾感染过程中，有利于终端效应CD4T细胞的产生，但代价是保护， 记忆前体CD4T细胞。我们将阐明导致这一现象的细胞因子和信号通路。 反应，检查T滤泡辅助细胞(TFH)的作用及其为B和T提供帮助的能力 细胞，并分析T细胞的耗竭。目的3.评价PMIF中和的治疗潜力 在疟疾。我们将探讨PMIF中和对小鼠血期和血液学模型的影响。 子孢子感染。我们的方法将包括通过一种新的自我放大的RNA用PMIF进行免疫 疫苗和基于我们发现的选择性的小分子抑制物的药理学策略 PMIF。 这些研究将提供关于疟原虫如何引导宿主炎症反应的洞察 干扰保护性免疫，并提出治疗性免疫调节和 疫苗研发。这项工作的结论可能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，它们各自产生紧密同源的MIF蛋白。

PROJECT SUMMARY / ABSTRACT 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.