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

作为先天免疫系统的一部分，人类补体是抵御微生物入侵的第一道防线。然而，大量的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的识别和破坏。尽管补体逃避在其他病原体中得到了广泛的研究，但对恶性疟原虫的这种过程知之甚少。恶性疟原虫是导致致命的热带疟疾的寄生虫。在我们之前的项目框架内，我们表明，人类补体的替代途径对恶性疟原虫红细胞内复制阶段的血液阶段以及在血餐后几分钟在蚊子中肠中形成的新配子构成严重威胁。在宿主-寄生虫的共同进化过程中，恶性疟原虫进化出多种分子逃避机制，以避免补体的攻击。我们的研究表明，细胞外的裂殖子和配子，以及红细胞内的裂殖体，都与其表面的人类调节因子H(FH)结合，导致补体因子C3b失活，从而抑制替代补体途径。有趣的是，无性血液阶段进一步结合了FH相关蛋白FHR-1，它的获得导致了两种相反的功能。根据FHR-1的结合部位，与受感染的红细胞的相互作用要么下调FH介导的补体逃避，导致寄生虫生存能力降低，要么增强人类宿主的炎症反应，从而在疟疾发病机制中发挥重要作用。根据迄今已有的数据，我们推测FH家族的蛋白在与恶性疟原虫的血液和性阶段相互作用时发挥着不同的功能，这对寄生虫或人类宿主都有利。因此，这项提案的总体目标是揭示FH家族蛋白在恶性疟原虫感染过程中的多种作用。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的生存并提供对补体攻击的保护；(2)详细研究FHR-1在调节疟疾发病机制中的作用；以及(3)表征FH和FHR-1的疟原虫受体作为干预策略的潜在靶点。通过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，并突出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补体逃逸分子作为疫苗靶点。

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.