Abstract
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.
Highlights
Malaria pathology is caused by asexual replication of apicomplexan parasites Plasmodium in the host bloodstream, but transmission between hosts requires sexual replication of parasites within mosquitoes
Two key regulators have been identified in the rodent malaria parasite Plasmodium berghei: the cyclin-dependent kinase CDPK4 controls the initiation of genome replication [5] while a downstream mitogen-activated protein kinase, map-2, regulates the onset of cytokinesis and release of microgametes [6,7]
We characterized the first protein with paternal effect on the development of malaria parasites in the mosquito
Summary
Malaria pathology is caused by asexual replication of apicomplexan parasites Plasmodium in the host bloodstream, but transmission between hosts requires sexual replication of parasites within mosquitoes. Mature gametocytes are arrested in development until their uptake by a female mosquito during her blood meal. These cells reportedly have increased DNA content that may suggest selective gene amplification since genome replication does not occur during gametocytogenesis [1,2,3]. Karyokinesis and cytokinesis, and consequent release of eight gametes are facilitated by cytoplasmic axonemes, each of which pulls one genome copy into the developing flagellate microgamete [4]. This process is known as exflagellation and regulated by calcium-dependent signaling. In parallel, activated female gametes (macrogametes) enlarge and emerge from the red blood cells
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