Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF

描述（申请人提供）：不能获得针对疟原虫的完全保护性免疫是疟疾控制的主要障碍。高水平的炎性细胞因子可以抑制模型系统中的记忆T细胞发育。值得注意的是，已发现所有疟原虫物种编码上游炎性细胞因子巨噬细胞迁移抑制因子（MIF）的直系同源物。疟原虫MIF（PMIF）在感染期间上调炎症反应，导致增强的活化诱导的T细胞凋亡和较少的抗原经历的成为记忆细胞的CD 4 T细胞。这一发现表明，疟原虫积极干扰疟疾特异性记忆CD 4 T细胞的产生，使寄生虫的持久性和传播。 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，我们将确定PMIF在抗疟疾免疫应答中的具体作用，具体目标如下：目标1。定义疟原虫编码的MIF（PMIF）促炎性激活免疫反应的分子基础。我们推测PMIF通过激活宿主MIF受体增加炎症反应。我们将定义PMIF与宿主MIF的共享和独特的信号传导特性，并研究保守的N-末端区域的作用，该区域介导与MIF受体的结合。我们将研究PMIF对Toll样和NOD样受体激活途径的作用，并将在感染缺乏mif基因的伯氏疟原虫ANKA株的小鼠中验证我们的观察结果。目标2.定义PMIF抑制抗疟疾适应性免疫应答的细胞和分子基础。我们推测，在疟疾感染期间，强烈的促炎环境有利于产生终末效应CD 4 T细胞，而牺牲了保护性记忆前体CD 4 T细胞。我们将阐明负责这种反应的细胞因子和信号通路，检查T滤泡辅助细胞（TFH）的作用及其为B和T细胞提供帮助的能力，并分析T细胞耗竭。目标3。评估PMIF中和疟疾的治疗潜力。我们将探讨PMIF的中和作用在血液阶段和子孢子感染的小鼠模型中的影响。我们的方法将包括免疫与PMIF的一种新的自扩增RNA疫苗和药理学策略的基础上，我们发现的选择性，小分子抑制剂PMIF。 这些研究将提供深入了解疟原虫如何指导宿主炎症反应，干扰保护性免疫，并提出新的治疗性免疫调节和疫苗开发的战略。从这项工作的结论可以推广到其他寄生虫病原体，如利什曼原虫，钩虫，布鲁日，产生自己的密切同源的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.