IntracellularPlasmodiumaquaporin 2 is required for sporozoite production in the mosquito vector and malaria transmission

Malaria remains a devastating disease and, with current measures failing to control its transmission, there is a need for novel interventions. A family of proteins that have long been pursued as potential intervention targets are aquaporins which are channels facilitating the movement of water and other solutes across membranes. We identify a new aquaporin in malaria parasites and demonstrate that it is essential for disease transmission through mosquitoes. Disruption of AQP2 in the human parasitePlasmodium falciparumand the rodent parasitePlasmodium bergheiblocks sporozoite production inside oocysts established on mosquito midguts, preventing parasite infection of salivary glands and transmission to a new host.In vivoepitope tagging of AQP2 inP. berghei, combined with immunofluorescence assays, reveals that the protein is localized in previously uncharacterized organelles found in the cytoplasm of gametocytes, ookinetes and sporozoites. The number of these organelles varies between individual parasites and lifecycle stages suggesting that they are likely part of a dynamic endolysosomal system. Phylogenetic analysis confirms that AQP2 is unique to malaria and closely related parasites and most closely related to other intracellular aquaporins. Structure prediction analyses identify several unusual features, including a large accessory extracellular loop and an arginine-to-phenylalanine substitution in the selectivity filter principally determining pore function, a unique feature not found in any aquaporins studied to date. This in conjunction with the requirement of AQP2 for malaria transmission suggests that AQP2 may be a fruitful new target of novel antimalarial interventions.