Malaria parasites utilize two essential plasma membrane fusogens for gamete fertilization

Abstract

Cell fusion of female and male gametes is the climax of sexual reproduction. In many organisms, the Hapless 2 (HAP2) family of proteins play a critical role in gamete fusion. We find that Plasmodium falciparum , the causative agent of human malaria, expresses two HAP2 proteins: Pf HAP2 and Pf HAP2p. These proteins are present in stage V gametocytes and localize throughout the flagellum of male gametes. Gene deletion analysis and genetic crosses show that Pf HAP2 and Pf HAP2p individually are essential for male fertility and thereby, parasite transmission to the mosquito. Using a cell fusion assay, we demonstrate that Pf HAP2 and Pf HAP2p are both authentic plasma membrane fusogens. Our results establish nonredundant essential roles for Pf HAP2 and Pf HAP2p in mediating gamete fusion in Plasmodium and suggest avenues in the design of novel strategies to prevent malaria parasite transmission from humans to mosquitoes. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04583-w.

A novel function for the sperm adhesion protein IZUMO1 in cell–cell fusion

“…Additionally, the fact that other eukaryotic fusogens (e.g., EFF-1, AFF-1, and GCS1) were shown to be less efficient in vitro than their viral counterparts ( Avinoam et al, 2011 ; Valansi et al, 2017 ; Kumar et al, 2022 ) may explain why previous studies failed to detect fusion of somatic cells expressing IZUMO1 and JUNO ( Bianchi et al, 2014 ).…”

“…GCS1 is also essential to fuse gametes in the malaria parasite Plasmodium , in the slime mold Dictyostelium , and in the algae Chlamydomonas ( Liu et al, 2008 ; Hirai et al, 2008 ; Okamoto et al, 2016 ). It was subsequently demonstrated that the expression of A. thaliana and Plasmodium falciparum GCS1 is sufficient to fuse mammalian cells in culture ( Valansi et al, 2017 ; Kumar et al, 2022 ); thereby GCS1 is a bona fide fusogen. GCS1 structure is similar to class II viral glycoproteins (e.g., rubella and zika viruses; Fédry et al, 2017 ; Pinello et al, 2017 ; Valansi et al, 2017 ; Feng et al, 2022 ) and fusion family (FF) proteins from nematodes and other organisms ( Mohler et al, 2002 ; Sapir et al, 2007 ; Pérez-Vargas et al, 2014 ).…”

HOP1 and HAP2 are conserved components of the meiosis-related machinery required for successful mating in Leishmania

“…In P. falciparum, HAP2 is expressed throughout the plasma membrane of male gametocytes beginning at stage II of development, and in fully differentiated microgametes. Its paralog, HAP2p, shows a patchier membrane expression pattern, and begins to be expressed later during gametocyte development, and interestingly on stage V female gametocytes 50 . Whether HAP2p functions bilaterally to promote gamete fusion in P. falciparum, as described here for HAP2-2 in L. tropica, has not been addressed.…”

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

“…Pf s47 plays an important role in protecting ookinetes from mosquito’s immune system, Pf s47 could be a potential TBV candidate ( 93 ). The Hapless 2 (HAP2) family of proteins play a critical role in gamete fusion, and immunization with protein fragments of Pf HAP2, Pf HAP2p and Pb HAP2 generated transmission-blocking activity ( 150 , 151 ). Recombinant Pb HAP2 protein administered in rabbits showed high immunogenicity by inducing HAP2-specific antibodies which inhibited in vitro ookinete formation and oocyst formation in Anopheles midgut ( 151 ).…”