Targeting the AgMOBP1-PfSyn5 mosquito-parasite interface completely blocks malaria transmission

Malaria control remains constrained by an incomplete understanding of the molecular interactions that enable Plasmodium falciparum transmission within mosquito vectors. Although blood-stage parasite biology has been extensively studied, the mosquito-stage processes required for transmission are less well defined. Here, we characterize a previously unannotated Anopheles gambiae midgut factor, Midgut Ookinete Binding Protein 1 (AgMOBP1; AGAP008138), and define its role in parasite infection. AgMOBP1 is a membrane-associated protein localized predominantly to the apical surface of midgut epithelial cells, is induced by blood feeding, and appears restricted to anopheline mosquitoes. Functional infection assays showed that exogenous recombinant AgMOBP1 enhanced Plasmodium infectivity by increasing midgut oocyst burden, whereas anti-AgMOBP1 antibodies significantly reduced infection, establishing AgMOBP1 as a host factor that promotes transmission. Using biochemical interaction assays, we identified the parasite binding partner of AgMOBP1 as the P. falciparum syntaxin-5-like protein PfSyn5. Disruption of this interaction with anti-PfSyn5 polyclonal antibodies produced exceptionally potent transmission-blocking activity, with complete inhibition at 1 {micro}g/mL and an estimated IC50 of [~]3 ng/mL ([~]20 pM). This potency is approximately one million-fold lower than the total IgG concentration in normal human plasma. Together, these findings identify a critical mosquito-parasite molecular interface required for malaria transmission and establish the AgMOBP1-PfSyn5 axis as a promising target for transmission-blocking vaccines, monoclonal antibodies, and other intervention strategies. Significance StatementInterrupting malaria transmission requires a deeper mechanistic understanding of how Plasmodium parasites interact with their mosquito vectors. Here, we define a previously uncharacterized mosquito midgut factor, AgMOBP1, and identify its parasite binding partner, the Plasmodium falciparum membrane protein PfSyn5. We show that this molecular interaction is required for efficient parasite transmission to Anopheles mosquitoes. Remarkably, antibodies against PfSyn5 completely blocked transmission at low concentrations, revealing exceptional functional potency. These findings uncover a previously unknown mosquito-parasite invasion pathway and establish the AgMOBP1-PfSyn5 interface as a high-value target for transmission-blocking vaccines, monoclonal antibodies, and next-generation malaria control strategies.