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: 10614419
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614419
• 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; Legal patent; Leishmania; Liver; Malaria; Malaria Vaccines; Memory; Memory B-Lymphocyte; Metabolism; Migration Inhibitory Factor; Mus; Orthologous Gene; Parasites; Pathway interactions; 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; circumsporozoite; cytokine; filaria; immunoregulation; improved; inhibitor; insight; malaria infection; memory CD4 T lymphocyte; mouse model; novel; novel therapeutic intervention; novel therapeutics; novel vaccines; pathogen; pharmacologic; 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.

项目摘要 不能获得针对疟原虫的保护性免疫是疟疾的主要障碍 控制在之前的资助期间，我们发现宿主细胞因子的疟原虫直系同源物 巨噬细胞移动抑制因子，称为PMIF，损害生发中心的形成， T滤泡辅助细胞（Tfh）的分化，导致记忆B和T淋巴细胞的发育减少。 细胞我们通过用pmif RNA疫苗接种伯氏疟原虫株， 复制子，其延迟血液期开放，增强Tfh细胞和生发中心反应， 增强记忆性CD 4和肝脏驻留的环子孢子特异性CD 8 T细胞的分化。我们 观察到感染控制的改善和对再次感染的完全保护， 从pmif RNA复制子免疫的宿主过继转移CD 8或CD 4 T细胞。我们的数据表明 疟原虫利用PMIF，这表明严格的进化保守，干扰 免疫记忆我们提出以下具体目标，以实现我们更好地了解的目标 对疟疾的无效免疫，并为更好的疫苗提供基础：目标1。定义影响 以及PMIF中和宿主对环子孢子（CSP）反应的潜在协同作用 预防针在基于CSP的RTS，S疫苗中观察到的部分免疫力和免疫力减弱部分是由于 记忆T细胞反应不足我们假设CSP与PMIF疫苗接种相结合， 将T细胞存储器增加到CSP，并提供最佳和高级别保护。我们会研究这个方法 与沃尔特里德陆军研究所合作， 与恶性疟原虫疟疾疫苗-013（FMP 013）一起在人CSP转基因伯氏疟原虫小鼠中 模型目标2.定义PMIF对疟原虫肝脏阶段发育的影响。PMIF还 支持最初的子孢子感染和肝脏阶段的寄生虫发展的生存信号，通过 肝细胞MIF受体，CD 74。我们假设PMIF重新编程肝细胞代谢， 抑制受感染肝细胞的宿主保护性凋亡。我们将阐明所涉及的途径， 更好地定义肝脏阶段PMIF表达对免疫应答发展的影响。目标3. 评价新型小分子PMIF抑制剂的治疗潜力。我们已经开发出一种 第一种小分子26 k，通过宿主MIF受体选择性阻断PMIF信号传导 CD 74，减少肝脏阶段寄生虫负担，并完全保护小鼠免受脑型疟疾。我们假设 药理学PMIF拮抗作用与26 k可能是一种易于控制的预防方法， 治疗，并可能增加免疫记忆反应。更深入地了解PMIF途径将 导致更好的疟疾治疗和疫苗开发策略，并可能推广 其他表达邻位MIF蛋白的寄生虫。

项目成果

MIF contributes to Trypanosoma brucei associated immunopathogenicity development.

MIF 有助于布氏锥虫相关免疫致病性的发展。

• DOI: 10.1371/journal.ppat.1004414
• 发表时间: 2014
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Stijlemans,Benoît;Leng,Lin;Brys,Lea;Sparkes,Amanda;Vansintjan,Liese;Caljon,Guy;Raes,Geert;VanDenAbbeele,Jan;VanGinderachter,JoA;Beschin,Alain;Bucala,Richard;DeBaetselier,Patrick
• 通讯作者: DeBaetselier,Patrick

Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection.

• DOI: 10.1038/s41467-018-05041-7
• 发表时间: 2018-07-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Baeza Garcia A;Siu E;Sun T;Exler V;Brito L;Hekele A;Otten G;Augustijn K;Janse CJ;Ulmer JB;Bernhagen J;Fikrig E;Geall A;Bucala R
• 通讯作者: Bucala R

Ostertagia ostertagi macrophage migration inhibitory factor is present in all developmental stages and may cross-regulate host functions through interaction with the host receptor.

Ostertagia ostertagi 巨噬细胞迁移抑制因子存在于所有发育阶段，并可能通过与宿主受体相互作用交叉调节宿主功能。

• DOI: 10.1016/j.ijpara.2014.01.009
• 发表时间: 2014
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: Qu,Guanggang;Fetterer,Raymond;Leng,Lin;Du,Xin;Zarlenga,Dante;Shen,Zhiqiang;Han,Wenyu;Bucala,Richard;Tuo,Wenbin
• 通讯作者: Tuo,Wenbin

Suppression of Plasmodium MIF-CD74 signaling protects against severe malaria.

• DOI: 10.1096/fj.202101072r
• 发表时间: 2021-12
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

The non-mammalian MIF superfamily.

• DOI: 10.1016/j.imbio.2016.10.006
• 发表时间: 2017-03
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Sparkes A;De Baetselier P;Roelants K;De Trez C;Magez S;Van Ginderachter JA;Raes G;Bucala R;Stijlemans B
• 通讯作者: Stijlemans B