The multiple roles of the factor H protein family during malaria infection

H因子蛋白家族在疟疾感染过程中的多重作用

• 批准号: 325507782
• 负责人: Professorin Dr. Gabriele Pradel
• 金额: --
• 依托单位: Abteilung für Zelluläre und Angewandte Infektionsbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/325507782?language=en
• 关键词: multiple; roles; factor; protein; family

As part of the innate immune system, the human complement is a first line of defence against microbial invaders. However, a high number of microbes can evade complement recognition and destruction by binding regulator proteins that normally protect self-cells from complement activation. Although complement evasion has been studied extensively in other pathogens, little is known about such processes in Plasmodium falciparum, the parasite responsible for the deadly malaria tropica. Within the framework of our previous project we showed that the alternative pathway of human complement represents a severe threat for the P. falciparum blood stages during the intraerythrocytic replication phase as well as for the emerging gametes that form in the mosquito midgut minutes after the blood meal. In the course of host-parasite coevolution, P. falciparum has evolved a variety of molecular evasion mechanisms to avoid attack by the complement. Our studies showed that the extracellular merozoites and gametes, but also the intraerythrocytic schizonts bind the human regulator factor H (FH) on their surfaces, leading to inactivation of complement factor C3b and hence inhibition of the alternative complement pathway. Interestingly, the asexual blood stages further bind the FH-related protein FHR-1 and its acquisition results in two opposing functions. Depending on the binding site of FHR-1, the interaction with infected red blood cells either downregulates FH-mediated complement evasion, resulting in reduced viability of the parasite, or enhances inflammatory responses in the human host with strong effects on malaria pathogenesis. In view of the available data to date we hypothesize that the proteins of the FH family exert various functions, when interacting with the P. falciparum blood and sexual stages, which benefit either the parasite or the human host. It is therefore the overall objective of this proposal to unveil the multiple roles of the FH family proteins during P. falciparum infection. For this purpose, we aim to (1) unveil how malaria parasites co-opt FH family proteins to promote parasite viability and to provide protection against complement attack; (2) investigate in detail the role of FHR-1 in modulating malaria pathogenesis; and (3) characterize plasmodial receptors of FH and FHR-1 as potential targets for interventional strategies. Data gained by this study will provide in-depth knowledge of the plasmodial complement evasion machinery and highlight the molecular link between FH family proteins and the outcome of malaria infection. The data will further help us to evaluate complement evasion molecules as vaccine targets.

作为先天免疫系统的一部分，人体补体是抵御微生物入侵的第一道防线。然而，大量微生物可以通过结合通常保护自身细胞免受补体激活的调节蛋白来逃避补体识别和​​破坏。尽管补体逃避已在其他病原体中进行了广泛研究，但对恶性疟原虫（导致致命的热带疟疾的寄生虫）的这种过程知之甚少。在我们之前项目的框架内，我们表明，人类补体的替代途径对红细胞内复制阶段的恶性疟原虫血液阶段以及吸血后几分钟在蚊子中肠中形成的新兴配子构成严重威胁。在宿主-寄生虫共同进化的过程中，恶性疟原虫进化出了多种分子逃避机制，以避免补体的攻击。我们的研究表明，细胞外裂殖子和配子以及红细胞内裂殖体在其表面结合人类调节因子 H (FH)，导致补体因子 C3b 失活，从而抑制补体旁路途径。有趣的是，无性血液阶段进一步结合FH相关蛋白FHR-1，其获得导致两种相反的功能。根据 FHR-1 的结合位点，与受感染红细胞的相互作用要么下调 FH 介导的补体逃逸，导致寄生虫活力降低，要么增强人类宿主的炎症反应，对疟疾发病机制产生强烈影响。鉴于迄今为止的可用数据，我们假设 FH 家族的蛋白质在与恶性疟原虫血液和性阶段相互作用时发挥各种功能，这对寄生虫或人类宿主都有好处。因此，本提案的总体目标是揭示 FH 家族蛋白在恶性疟原虫感染期间的多重作用。为此，我们的目标是 (1) 揭示疟疾寄生虫如何利用 FH 家族蛋白来促进寄生虫活力并提供针对补体攻击的保护； (2)详细研究FHR-1在调节疟疾发病机制中的作用； (3) 将 FH 和 FHR-1 的疟原虫受体表征为干预策略的潜在靶标。这项研究获得的数据将提供对疟原虫补体逃避机制的深入了解，并强调 FH 家族蛋白与疟疾感染结果之间的分子联系。这些数据将进一步帮助我们评估作为疫苗靶点的补体逃避分子。