Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF

疟原虫 MIF 对适应性免疫的炎症抑制

• 批准号: 8822823
• 负责人: RICHARD J BUCALA
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822823
• 关键词: Accounting; Antigens; Antimalarials; Apoptosis; Binding; Binding Proteins; Biological Models; Blood; Brugia; CD4 Positive T Lymphocytes; CD44 gene; Cells; Cessation of life; Communicable Diseases; Cytokine Signaling; Data; Development; Environment; Erythrocytes; Evaluation; Foundations; Generations; Genes; Genomics; Goals; Health; Helper-Inducer T-Lymphocyte; Hookworms; Human; Immune response; Immunity; Immunization; Infection; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lead; Leishmania; Malaria; Malaria Vaccines; Mediating; Memory; Migration Inhibitory Factor; Molecular; Mus; N-terminal; Orthologous Gene; Parasitemia; Parasites; Pathway interactions; Plasmodium; Production; Property; Proteins; RNA; Receptor Activation; Research; Role; Signal Pathway; Signal Transduction; Sporozoites; Staging; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Therapeutic; Toll-like receptors; Transducers; Vaccine Therapy; Vaccines; Work; adaptive immunity; base; cytokine; design; exhaustion; experience; filaria; immunoregulation; inhibitor/antagonist; insight; memory CD4 T lymphocyte; mouse model; novel; novel therapeutic intervention; pathogen; phenylpyruvate tautomerase; receptor; response; small molecule; transmission process; vaccine development

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.

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控制疟疾的主要障碍。高水平的炎性细胞因子可以抑制模型系统中的记忆T细胞的发展。值得注意的是，已经发现所有疟原虫都编码上游炎症细胞因子，巨噬细胞迁移抑制因子（MIF）的直系同源物。 MIF疟原虫（PMIF）在感染过程中上调炎症反应，从而增强了激活诱导的T细胞凋亡，而较少的抗原抗原CD4 T细胞成为记忆细胞。这一发现表明，疟原虫会积极干扰疟疾特异性记忆CD4 T细胞的产生，以实现寄生虫的持久性和传播。 为了更好地理解对疟疾的无效免疫力并为更好的疫苗提供基础，我们将在三个特定目的中确定PMIF在抗疟疾免疫反应中的特定作用，如下：AIM 1。定义疟原虫膜状膜片膜片的MIF（PMIF）免疫反应的促炎性激活的分子基础。我们假设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，并检查保守的N末端区域的作用，该区域介导与MIF受体结合。我们将研究PMIF对Toll样和点头样受体激活途径的作用，并将验证我们在缺乏MIF基因的伯格氏疟原虫Anka菌株中感染的小鼠中的观察结果。 AIM 2。定义细胞和分子基础，以抑制PMIF抑制抗疟疾自适应免疫反应。我们假设疟疾感染期间强烈的促炎环境有利于终端效应子CD4 T细胞的产生，而牺牲了保护性记忆前体CD4 T细胞。我们将阐明负责此反应的细胞因子和信号传导途径，检查T卵泡辅助细胞（TFH）的作用及其为B和T细胞提供帮助的能力，并分析T细胞耗尽。 AIM 3。评估疟疾中中和的治疗潜力。我们将探讨PMIF在血液阶段和孢子岩感染的小鼠模型中中和的影响。我们的方法将包括新型自我扩增的RNA疫苗对PMIF进行免疫接种和基于我们发现PMIF的选择性小分子抑制剂的药理策略。 这些研究将洞悉疟原虫如何将宿主炎症反应引导到干扰保护性免疫，并提出用于治疗性免疫调节和疫苗开发的新策略。这项工作的结论可能会推广到其他寄生虫病原体，例如利什曼原虫，AncyClostoma和Brugia，它们产生了自己的紧密同源MIF蛋白。