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: 8664206
• 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/8664206
• 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; 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; public health relevance; receptor; response; small molecule; transmission process; vaccine development

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.

项目摘要/摘要 不能获得对疟原虫的完全保护性免疫是疟疾的主要障碍 控制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，已经发现所有疟原虫物种编码上游炎性细胞因子的直系同源物。 细胞因子、巨噬细胞移动抑制因子（MIF）。疟原虫MIF（PMIF）上调炎症反应 感染期间的反应，导致增强的活化诱导的T细胞凋亡和更少的抗原- CD 4 T细胞变成记忆细胞。这一发现表明，疟原虫积极干扰 随着疟疾特异性记忆CD 4 T细胞的产生，使寄生虫能够持续存在， 传输 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在三个特定目的中的抗疟疾免疫应答中的特定作用， 目标1.定义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增加了炎症反应， 通过激活宿主的MIF受体来进行反应。我们将定义共享和独特的信令属性， PMIF与宿主MIF的比较，并检查保守的N-末端区域的作用，该区域介导与 MIF受体。我们将研究PMIF对Toll样和NOD样受体激活的作用 途径，我们将验证我们在感染伯氏疟原虫ANKA菌株的小鼠中的观察结果， mif基因。目标2.确定抑制抗疟药物的细胞和分子基础 通过PMIF的适应性免疫应答。我们假设强烈的促炎环境 在疟疾感染期间，以保护性T细胞为代价， 记忆前体CD 4 T细胞。我们将阐明细胞因子和信号通路负责这一点 反应，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。 细胞，并分析T细胞耗竭。目标3。评价PMIF中和的治疗潜力 在疟疾。我们将探索PMIF中和在小鼠血液阶段模型中的影响， 子孢子感染我们的方法将包括免疫与PMIF通过一种新的自我扩增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的炎症反应， 干扰保护性免疫并提出治疗性免疫调节新策略， 疫苗研发。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、钩口线虫和布鲁日丝虫，它们产生它们自己的密切同源的MIF蛋白。