title: The Plasmodium falciparum blood stages acquire factor H family proteins to evade destruction by human complement.
abstract: The acquisition of regulatory proteins is a means of blood-borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL-1 and CFHR-1 to their surface, and FH binding is trypsin-resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH-mediated protection via anti-FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target.
authors.affiliation: Division of Cellular and Applied Infection Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany.
authors.forename: Thiago F A
authors.initials: TF
authors.lastname: Rosa
authors.affiliation: Division of Cellular and Applied Infection Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Flammersfeld
authors.affiliation: Division of Cellular and Applied Infection Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany.
authors.forename: Che J
authors.initials: CJ
authors.lastname: Ngwa
authors.affiliation: Division of Cellular and Applied Infection Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Kiesow
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology, Forckenbeckstr. 6, 52074, Aachen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Beutenbergstr. 11a, 07745, Jena, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Beutenbergstr. 11a, 07745, Jena, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.affiliation: Division of Cellular and Applied Infection Biology, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology, Forckenbeckstr. 6, 52074, Aachen, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
mesh_terms: D017242:Complement Factor H / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D010963:Plasmodium falciparum / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D017242:Complement Factor H; D003165:Complement System Proteins