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

Abstract

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.

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…To evaluate a potential role of FH in protection against the ACP‐mediated growth impairment, schizont‐iRBC cultures at a parasitemia of 2.5% were incubated with 20 vol% NHS in the presence of a mAb directed against FH modules CCP8‐15 known to exhibit functional inhibition of the complement regulator (Oppermann et al , 2006; Simon et al , 2013) at a concentration of 100 µg ml −1 . Controls were incubated with NHS or HIS without mAb anti‐FH or with Albumax‐supplemented cell culture medium.…”

“…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). …”

“…Read et al , 1994; Williamson et al , 1995; Healer et al , 1997; Beiss et al , 2015; Boes et al , 2015; reviewed in Pradel, 2007). Furthermore, in the presence of anti‐Pfs230 antibodies complement factor C1q binds to the gamete surface and activates the classical complement pathway (Simon et al , 2013). …”

“…In a recent study, we identified FH as the factor responsible for protecting the extracellular gametes of Plasmodium falciparum from ACP‐mediated lysis (Simon et al , 2013). We showed that human complement is active in the mosquito midgut for 1 h after the blood meal and during this time represents a severe threat to the emerging gametes.…”

The development of malaria parasites in the mosquito midgut

“…Gametocytes possess an inner membrane complex (IMC) underneath their plasmalemma, which consists of flat membranous sacs, the alveoli, and supporting structural elements and which is thought to be required for the stability of the crescent‐shaped parasite stages (Dearnley et al ., 2012; Kono et al ., 2012; Simon et al ., 2013; reviewed in Harding and Meissner, 2014; Boucher and Bosch, 2015). During gametogenesis, the IMC disintegrates, resulting in gametes solely confined by the plasmalemma.…”