Abstract
ABSTRACTMosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission. Mosquito infection ensues upon oocyst development that follows ookinete invasion and traversal of the mosquito midgut epithelium. Here, we report the characterization of PIMMS2 (Plasmodium invasion of mosquito midgut screen candidate 2), a Plasmodium berghei protein with structural similarities to subtilisin-like proteins. PIMMS2 orthologs are present in the genomes of all plasmodia and are mapped between the subtilisin-encoding genes SUB1 and SUB3. P. berghei PIMMS2 is specifically expressed in zygotes and ookinetes and is localized on the ookinete surface. Loss of PIMMS2 function through gene disruption by homologous recombination leads to normal development of motile ookinetes that exhibit a severely impaired capacity to traverse the mosquito midgut and transform to oocysts. Genetic complementation of the disrupted locus with a mutated PIMMS2 allele reveals that amino acid residues corresponding to the putative subtilisin-like catalytic triad are important but not essential for protein function. Our data demonstrate that PIMMS2 is a novel ookinete-specific protein that promotes parasite traversal of the mosquito midgut epithelium and establishment of mosquito infection.
Highlights
Mosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission
Berghei in the A. gambiae midgut previously identified several genes expressed during ookinete development and midgut epithelium traversal [11]
The results showed that the oocyst numbers were significantly reduced in Δpbpimms2 compared to c507 controls, reflecting a strong defect in either ookinete motility or midgut invasion capacity (Fig. 2D and Table S1)
Summary
Mosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission. Ookinete midgut traversal and transformation to oocysts is associated with de novo protein synthesis in developing ookinetes, which are thought to be important for host cell recognition, binding, and motility. They include the circumsporozoite and TRAPrelated protein (CTRP [4, 5]), chitinase (CHT1 [6]), the secreted ookinete adhesive protein (SOAP [7]), the von Willebrand factor A domain-related protein (WARP [8]), and the perforin-like proteins 3 (PPLP3) [9] and PPLP5 [10]. We use homologous recombination to disrupt the PIMMS2 genomic locus and study the function of the protein during parasite development and mosquito infection, and we reveal that PIMMS2 promotes midgut epithelium traversal. We use genetic complementation to investigate the relevance of the subtilisin-like structural homology to the function of PIMMS2 and show that conserved amino acid residues corresponding to the catalytic triad of other known subtilisin-like proteins are important but not essential for the function of PIMMS2
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