Paternal effect of the nuclear formin-like protein MISFIT on Plasmodium development in the mosquito vector

Malaria parasites must undergo sexual and sporogonic development in mosquitoes before they can infect their vertebrate hosts. We report the discovery and characterization of MISFIT, the first protein with paternal effect on the development of the rodent malaria parasite Plasmodium berghei in Anopheles mosquitoes. MISFIT is expressed in male gametocytes and localizes to the nuclei of male gametocytes, zygotes and ookinetes. Gene disruption results in mutant ookinetes with reduced genome content, microneme defects and altered transcriptional profiles of putative cell cycle regulators, which yet successfully invade the mosquito midgut. However, developmental arrest ensues during the ookinete transformation to oocysts leading to malaria transmission blockade. Genetic crosses between misfit mutant parasites and parasites that are either male or female gamete deficient reveal a strict requirement for a male misfit allele. MISFIT belongs to the family of formin-like proteins, which are known regulators of the dynamic remodeling of actin and microtubule networks. Our data identify the ookinete-to-oocyst transition as a critical cell cycle checkpoint in Plasmodium development and lead us to hypothesize that MISFIT may be a regulator of cell cycle progression. This study offers a new perspective for understanding the male contribution to malaria parasite development in the mosquito vector.
Author Summary The unicellular protozoan parasites that cause malaria must undergo sexual development and subsequent proliferation in mosquitoes before they can infect humans and cause malaria. We characterized the first protein with paternal effect on the development of malaria parasites in the mosquito. This protein, which we named MISFIT, is produced in the progenitor cells of male gametes and found in the nuclei of these cells as well as in the nuclei of zygotes and their invasive forms, termed ookinetes. Disruption of the gene that encodes MISFIT leads to ookinetes with reduced DNA content, a defective secretory machinery and altered expression of various regulators of DNA replication and cell division. These mutant parasites stop developing immediately after traversing the mosquito gut, leading to malaria transmission blockage. Our study offers a new perspective for understanding the sexual development of malaria parasites in the mosquito vector, which leads to transmission of one of the most devastating diseases of mankind.