Targeting the mosquito prefoldin–chaperonin complex blocks Plasmodium transmission

Abstract

The Plasmodium infection cycle in mosquitoes relies on numerous host factors in the vector midgut, which can be targeted with therapeutics. The mosquito prefoldin complex is needed to fold proteins and macromolecular complexes properly. Here we show that the conserved Anopheles mosquito prefoldin (PFDN)–chaperonin system is a potent transmission-blocking target for multiple Plasmodium species. Silencing any prefoldin subunit or its CCT/TRiC partner via RNA interference reduces Plasmodium falciparum oocyst loads in the mosquito midgut, as does co-feeding mosquitoes with PFDN6-specific antibody and gametocytes. Inhibition of the PFDN–CCT/TRiC chaperonin complex results in the loss of epithelial and extracellular matrix integrity, which triggers microorganism-mediated anti-Plasmodium immune priming and compromises the parasite’s laminin-based immune evasion. Mouse malaria transmission-blocking vaccine and antibody co-feeding assays support its potential as a multispecies transmission-blocking target for P. falciparum and Plasmodium vivax. Further study is needed to determine the potential of this system as a transmission-blocking vaccine target. Disrupting the prefoldin–chaperonin complex in various species of Anopheles mosquitoes results in a compromised intestinal barrier leading to an immune response that inhibits the malaria parasite.