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: 10386832
• 负责人: RICHARD J BUCALA
• 金额: $ 41.88万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386832
• 关键词: Adoptive Transfer; Antibody titer measurement; Apoptosis; Blood; Brugia; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cerebral Malaria; Cessation of life; Collaborations; Communicable Diseases; Data; Development; Falciparum Malaria; Foundations; Funding; Genetic; Goals; Helper-Inducer T-Lymphocyte; Hepatocyte; Hookworms; Human; Immune response; Immunity; Immunize; Immunologic Memory; Impairment; Infection; Infection Control; Inflammatory; Inflammatory Response; Interferon Type II; Knowledge; Lead; Leishmania; Liver; Malaria; Malaria Vaccines; Memory; Memory B-Lymphocyte; Metabolism; Migration Inhibitory Factor; Mus; Orthologous Gene; Parasites; Pathway interactions; Pharmacology; Plasmodium; Prophylactic treatment; Proteins; Publishing; RNA; Replicon; Research; Research Institute; Role; Signal Pathway; Signal Transduction; Sporozoites; Structure of germinal center of lymph node; T cell response; T memory cell; T-Lymphocyte; Therapeutic; Transgenic Organisms; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Work; adaptive immunity; antagonist; base; circumsporozoite; cytokine; filaria; immunoregulation; improved; inhibitor; insight; malaria infection; memory CD4 T lymphocyte; mouse model; novel; novel therapeutic intervention; novel therapeutics; novel vaccines; pathogen; programs; receptor; response; small molecule; small molecule inhibitor; synergism; therapy development; vaccine development

PROJECT SUMMARY The inability to acquire protective immunity against Plasmodium is a major obstacle to malaria control. In the prior funding period, we showed that the Plasmodium orthologue of the host cytokine macrophage migration inhibitory factor, termed PMIF, impairs germinal center formation and the differentiation of T follicular helper cells (Tfh), leading to a reduction in the development of memory B and T cells. We recapitulated genetic PMIF deficiency in a P. berghei strain by vaccination with a pmif RNA replicon, which delayed blood-stage patency, augmented Tfh cell and germinal center responses, and enhanced the differentiation of memory CD4 and liver-resident, circumsporozoite-specific CD8 T cells. We observed improved control of infection and complete protection from re-infection, which was replicated by adoptive transfer of CD8 or CD4 T cells from pmif RNA replicon immunized hosts. Our data indicate that Plasmodium parasites utilize PMIF, which shows strict evolutionary conservation, to interfere with immunologic memory. We propose the following Specific Aims to achieve our goal of better understanding ineffective immunity to malaria and providing a foundation for better vaccines: Aim 1. Define the impact and potential synergy of PMIF neutralization in the host response to circumsporozoite (CSP) vaccination. The partial and waning immunity observed with the CSP-based RTS,S vaccine is due in part to an inadequate memory T cell response. We hypothesize that combining CSP with PMIF vaccination will increase T cell memory to CSP and provide optimal and high-level protection. We will study this approach in collaboration with the Walter Reed Army Institute of Research by immunizing mice against PMIF together with the Falciparum Malaria Vaccine-013 (FMP013) in a human CSP-transgenic P. berghei mouse model. Aim 2. Define the impact of PMIF on Plasmodium liver-stage development. PMIF also supports initial sporozoite infection and liver-stage parasite development by survival signaling through the hepatocellular MIF receptor, CD74. We hypothesize that PMIF re-programs hepatocyte metabolism to inhibit the host-protective apoptosis of infected hepatocytes. We will elucidate the pathways involved and better define the impact of liver-stage PMIF expression on the developing immune response. Aim 3. Evaluate the therapeutic potential of a novel small molecule PMIF inhibitor. We have developed a first-in-class small molecule, 26k, that selectively blocks PMIF signaling through the host MIF receptor CD74, reduces liver-stage parasite burden, and fully protects mice from cerebral malaria. We hypothesize that pharmacologic PMIF antagonism with 26k may be a tractable approach for prophylaxis and liver-stage treatment, and may augment immunologic memory responses. Closer knowledge of the PMIF pathway will lead to better strategies for malaria therapy and vaccine development, and potentially may be generalized to other parasites that express orthologous MIF proteins.

项目总结 无法获得对疟原虫的保护性免疫是疟疾的主要障碍。 控制力。在之前的资助期间，我们证明了疟原虫宿主细胞因子的同源基因 巨噬细胞移动抑制因子，称为PMIF，损害生发中心的形成和 T滤泡辅助细胞(TFH)的分化导致记忆B和T的发育减少 细胞。我们用pmif rna免疫一株伯氏疟原虫，概述了pmif的遗传缺陷。 复制子，它延迟了血液阶段的开放，增强了Tfh细胞和生发中心的反应，以及 促进记忆性CD4和驻留在肝脏的环子孢子特异性CD8T细胞的分化。我们 观察到改进的感染控制和完全防止再次感染，这一点得到了复制 过继转移PMIF RNA复制子免疫宿主的CD8或CD4T细胞。我们的数据表明 疟原虫利用PMIF进行干扰，PMIF表现出严格的进化保守性 免疫记忆。我们提出以下具体目标，以实现我们更好地理解 对疟疾的无效免疫并为更好的疫苗提供基础：目标1.确定其影响 以及PMIF中和在宿主对环子孢子(CSP)的反应中的潜在协同作用 接种疫苗。以CSP为基础的RTS观察到的部分和减弱的免疫，S疫苗是部分原因 记忆T细胞反应不足。我们假设将CSP与PMIF疫苗相结合将 将T细胞内存增加到CSP，并提供最佳和高级保护。我们会研究这个方法。 与沃尔特里德陆军研究所合作，通过对小鼠进行PMIF免疫 联合恶性疟原虫疫苗-013(FMP013)在人CSP转基因伯氏疟原虫小鼠中的应用 模特。目的2.明确PMIF对疟原虫肝期发育的影响。PMIF还 支持初始的子孢子感染和肝期寄生虫的发育，通过 肝细胞MIF受体，CD74。我们假设PMIF重新编程肝细胞代谢以 抑制感染肝细胞的宿主保护性细胞凋亡。我们将阐明所涉及的途径和 更好地确定肝期PMIF表达对发育中的免疫反应的影响。目标3. 评估一种新的小分子PMIF抑制剂的治疗潜力。我们已经开发出一种 一流的小分子，26K，选择性地阻断通过宿主MIF受体的PMIF信号 CD74，减少肝脏阶段的寄生虫负担，并充分保护小鼠免受脑型疟疾的侵袭。我们假设 用26k药理拮抗PMIF可能是预防和分期的一种简便方法。 治疗，并可能增强免疫记忆反应。对PMIF途径的更深入了解将 导致疟疾治疗和疫苗开发的更好战略，并有可能推广 其他表达同源MIF蛋白的寄生虫。