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

• Applicant: Professorin Dr. Gabriele Pradel
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325507782

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.

• DFG Programme: Research Grants