Malaria Parasites Co-opt Human Factor H to Prevent Complement-Mediated Lysis in the Mosquito Midgut

Research Center for Infectious Diseases, University of Würzburg, Josef-Schneider-Strasse 2/D15, 97080 Würzburg, Germany.
Cell host & microbe (Impact Factor: 12.33). 01/2013; 13(1):29-41. DOI: 10.1016/j.chom.2012.11.013
Source: PubMed


Human complement is a first line defense against infection in which circulating proteins initiate an enzyme cascade on the microbial surface that leads to phagocytosis and lysis. Various pathogens evade complement recognition by binding to regulator proteins that protect host cells from complement activation. We show that emerging gametes of the malaria parasite Plasmodium falciparum bind the host complement regulator factor H (FH) following transmission to the mosquito to protect from complement-mediated lysis by the blood meal. Human complement is active in the mosquito midgut for approximately 1 hr postfeeding. During this period, the gamete surface protein PfGAP50 binds to FH and uses surface-bound FH to inactivate the complement protein C3b. Loss of FH-mediated protection, either through neutralization of FH or blockade of PfGAP50, significantly impairs gametogenesis and inhibits parasite transmission to the mosquito. Thus, Plasmodium co-opts the protective host protein FH to evade complement-mediated lysis within the mosquito midgut.

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Available from: Gabriele Pradel, Oct 01, 2015
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    • "During this time, the IMC disintegrates to leave the newly formed gametes defined by a single membrane (Sologub et al., 2011). Consequently, antibodies directed against GAP50 are able to reduce FH binding to the gamete surface and inhibit parasite transmission from the human to the mosquito, making GAP50 a promising new candidate for transmission blocking vaccines (Simon et al., 2013). "
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    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. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Cellular Microbiology
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    • " native human serum together with anti - FH an - tibodies , mosquitoes were rendered resistant as parasite numbers were effectively reduced to zero ( Simon et al . 2013 ) . Co - immunoprecipitation assays with anti - FH an - tibodies on protein extracts from activated gametes in native human serum identified PfGAP50 as a parasite receptor for FH ( Simon et al . 2013 ) . However , the au - thors suggest that there are additional unknown FH re - ceptors on the surface of the gametes as anti - PfGAP50 antibodies only reduced the infectivity to mosquitoes by 38 - 60% . This hypothesis is plausible as other pathogens including Streptococcus pyogenes and Borrelia burg - dorferi use more than one surface "
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    ABSTRACT: Nearly one million people are killed every year by the malaria parasite Plasmodium. Although the disease-causing forms of the parasite exist only in the human blood, mosquitoes of the genus Anopheles are the obligate vector for transmission. Here, we review the parasite life cycle in the vector and highlight the human and mosquito contributions that limit malaria parasite development in the mosquito host. We address parasite killing in its mosquito host and bottlenecks in parasite numbers that might guide intervention strategies to prevent transmission.
    Full-text · Article · Apr 2014 · Memórias do Instituto Oswaldo Cruz
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    • "This delayed egress might provide the developing gamete with enough time to adapt to the mosquito midgut. Notably, we recently showed that following gametocyte activation the plasmodial transmembrane protein PfGAP50 relocates from the IMC to the PPM (Simon et al., 2013). Only after PfGAP50 is relocated to the PPM, the gametes exit the RBC. "
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    ABSTRACT: Egress of malaria parasites from the host cell requires the concerted rupture of its enveloping membranes. Hence, we investigated the role of the plasmodial perforin-like protein PPLP2 in the egress of Plasmodium falciparum from erythrocytes. PPLP2 is expressed in blood stage schizonts and mature gametocytes. The protein localizes in vesicular structures, which in activated gametocytes discharge PPLP2 in a calcium-dependent manner. PPLP2 comprises a MACPF domain and recombinant PPLP2 has hemolytic activities towards erythrocytes. PPLP2-deficient (PPLP2(-)) merozoites show normal egress dynamics during the erythrocytic replication cycle, but activated PPLP2(-) gametocytes were unable to leave erythrocytes and stayed trapped within these cells. While the parasitophorous vacuole membrane ruptured normally, the activated PPLP2(-) gametocytes were unable to permeabilize the erythrocyte membrane and to release the erythrocyte cytoplasm. In consequence, transmission of PPLP2(-) parasites to the Anopheles vector was reduced. Pore-forming equinatoxin II rescued both PPLP2(-) gametocyte exflagellation and parasite transmission. The pore sealant Tetronic 90R4, on the other hand, caused trapping of activated wild-type gametocytes within the enveloping erythrocytes, thus mimicking the PPLP2(-) loss-of-function phenotype. We propose that the hemolytic activity of PPLP2 is essential for gametocyte egress due to permeabilization of the erythrocyte membrane and depletion of the erythrocyte cytoplasm.
    Full-text · Article · Mar 2014 · Cellular Microbiology
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