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 无法获得完全保护性免疫质量的疟原虫是疟疾的主要障碍 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细胞的发展。 值得注意的是，已经发现所有疟原种都编码上游炎症的直系同源 细胞因子，巨噬细胞迁移抑制因子（MIF）。疟原虫MIF（PMIF）上调炎症 感染过程中的反应，导致激活诱导的T细胞凋亡增加，抗原较少 经历了成为存储单元的CD4 T细胞。这一发现表明疟原虫会主动干扰 随着疟疾特异性记忆CD4 T细胞的产生，使寄生虫持久性和 传播。 更好地了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标中确定PMIF在抗疟疾免疫反应中的特定作用，例如 以下内容：目标1。定义免疫促炎激活的分子基础 质子编码的MIF（PMIF）的响应。我们假设PMIF增加了炎症 通过激活宿主MIF受体来反应。我们将定义共享和唯一的信号属性 PMIF与宿主MIF并检查保守的N末端区域的作用，该区域介导了与 MIF受体。我们将研究PMIF对Toll样和点头样受体激活的作用 途径，我们将验证我们的观察结果，在缺乏其缺乏其的小鼠的小鼠中 MIF基因。目标2。定义抑制抗疟疾的细胞和分子基础 PMIF的自适应免疫反应。我们假设一个强大的促炎环境 在疟疾感染期间 记忆前体CD4 T细胞。我们将阐明负责此的细胞因子和信号通路 响应，检查T卵泡辅助细胞（TFH）的作用及其为B和T提供帮助的能力 细胞，并分析T细胞耗尽。目标3。评估PMIF中和的治疗潜力 在疟疾。我们将探讨PMIF在血阶段的小鼠模型中中和的影响 孢子岩感染。我们的方法将包括通过新型自我扩增的RNA对PMIF进行免疫接种 疫苗和药理学策略基于我们发现的选择性小分子抑制剂 PMIF。 这些研究将提供有关质量如何将宿主炎症反应引导到的洞察 干扰保护性免疫，并提出治疗性免疫调节的新策略和 疫苗开发。这项工作的结论可能会推广到其他寄生虫病原体，例如 Leishmania，AncyClostoma和Brugia产生了自己的紧密同源MIF蛋白。