DFG project: Factor H-mediated complement evasion by the malaria parasite
Duration: 3 years
Application period: since 2017
PIs: Gabriele Pradel and Christine Skerka (HKI Jena)
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. In the course of host-parasite coevolution, P. falciparum has developed a variety of molecular complement evasion mechanisms to assure both replication in the human erythrocytes as well as sexual reproduction in the midgut of the mosquito vector. Indeed, the human complement represents a severe threat for both the parasite blood and sexual stages, particularly for merozoites during red blood cell infection and for the emerging gametes that form in the mosquito midgut minutes after the blood meal. To evade complement-induced lysis, the asexual blood stages as well as the emerging gametes bind the human regulatory factor H (FH) to their surfaces, leading to inactivation of complement protein C3b. Besides FH, the factor H-like protein FHL1 is acquired by these stages, while the intraerythrocytic schizonts further bind the FH-related protein FHR1. Two plasmodial FH-receptors were hitherto identified; Pf92, which is exposed on the merozoite surface, and GAP50 that relocates from the inner membrane complex to the plasmalemma during gametogenesis. Functional impairment of these receptors results in increased complement-mediated killing of the respective parasite stage. On the basis of these findings, it is the objective to gain in-depth knowledge of FH-mediated complement evasion by P. falciparum during erythrocytic progeny and transmission by the mosquito. For this purpose we aim to 1) analyse the molecular fine regulation of plasmodial complement evasion as well as potential counteractive measures of the human immune system to overcome these evasion mechanisms; 2) conduct a cross-isolate and cross-species study on FH-mediated complement evasion to uncover potential variations in plasmodial complement evasion efficiencies and to identify parasite- or host-derived molecules responsible for these variations; and 3) identify additional FH-receptors of P. falciparum and characterize the FH-receptors as vaccine targets. Knowledge gained by this study will enable us to understand in more detail the driving force of complement evasion by blood-borne parasites in disease development. The expected results will further provide the basis for the design of malaria vaccines aimed to support complement-mediated lysis of the pathogen.