The impact of complement evasion on transmission of malaria

As part of the innate immune system, human complement is a first line of defence against microbial invaders. However, microbes can evade complement recognition by binding to regulator proteins that normally protect host cells from complement activation. Although complement evasion has been studied extensively in other pathogens, it has not been observed until recently in Plasmodium spp., the parasites responsible for the tropical disease malaria. In a new study, we identified a complement evasion mechanism in P. falciparum essential for parasite sexual reproduction, which takes places after their transmission from humans to mosquitoes. Together with the sexual precursor cells of malaria parasites, human complement is taken up during the blood meal of the mosquito, and in the mosquito midgut represents a threat to the emerging gametes. To avoid complement-induced lysis, the sexual-stage parasites bind the human regulatory factor H (FH) from the blood meal. Binding of FH to the sexual-stage surface involves the FH complement control protein module 7, which exhibits race- and region-dependent sequence variations related to autoimmune defects. FH binding is mediated by the plasmodial receptor GAP50, a transmembrane protein that is relocated from an internal compartment to the parasite plasma membrane during gametogenesis. The protection of the sexual stages by FH is necessary for their survival in the mosquito midgut, and the prevention of FH-binding using inhibitory antibodies results in complement-mediated destruction of the emerging gametes and thus in blocked parasite transmission to the mosquito. This newly-identified complement evasion mechanism opens novel avenues in combating malaria