Novel insights from the Plasmodium falciparum sporozoite-specific proteome by probabilistic integration of 26 studies

Abstract

Plasmodium species, the causative agent of malaria, have a complex life cycle involving two hosts. The sporozoite life stage is characterized by an extended phase in the mosquito salivary glands followed by free movement and rapid invasion of hepatocytes in the human host. This transmission stage has been the subject of many transcriptomics and proteomics studies and is also targeted by the most advanced malaria vaccine. We applied Bayesian data integration to determine which proteins are not only present in sporozoites but are also specific to that stage. Transcriptomic and proteomic Plasmodium data sets from 26 studies were weighted for how representative they are for sporozoites, based on a carefully assembled gold standard for Plasmodium falciparum (Pf) proteins known to be present or absent during the sporozoite life stage. Of 5418 Pf genes for which expression data were available at the RNA level or at the protein level, 975 were identified as enriched in sporozoites and 90 specific to them. We show that Pf sporozoites are enriched for proteins involved in type II fatty acid synthesis in the apicoplast and GPI anchor synthesis, but otherwise appear metabolically relatively inactive in the salivary glands of mosquitos. Newly annotated hypothetical sporozoite-specific and sporozoite-enriched proteins highlight sporozoite-specific functions. They include PF3D7_0104100 that we identified to be homologous to the prominin family, which in human has been related to a quiescent state of cancer cells. We document high levels of genetic variability for sporozoite proteins, specifically for sporozoite-specific proteins that elicit antibodies in the human host. Nevertheless, we can identify nine relatively well-conserved sporozoite proteins that elicit antibodies and that together can serve as markers for previous exposure. Our understanding of sporozoite biology benefits from identifying key pathways that are enriched during this life stage. This work can guide studies of molecular mechanisms underlying sporozoite biology and potential well-conserved targets for marker and drug development.

Iron transport pathways in the human malaria parasitePlasmodium falciparumrevealed by RNA-sequencing

“…3D). This observation is consistent with the fact that the extracellular portions of this protein are highly polymorphic due to their exposure to the immune system at the sporozoite stage (74). Interestingly, vaccines targeting Py E140 in Plasmodium yoelii were reported to induce up to 100% sterile protection mediated by antibodies in mice (101).…”

“…Pf E140 is predicted to be anchored in the parasite plasma membrane by a bundle of five transmembrane domains (74) and forms a coiled coil with a hydrophilic region that displays negatively charged patches exposed to the extracellular side (Fig. 5A and B).…”

A Prioritized and Validated Resource of Mitochondrial Proteins in Plasmodium Identifies Unique Biology

“…Here, we integrated eight data sets containing proteomic data, gene expression data, data on orthology to mitochondrial proteins from other species, phylogenetic distribution data, and amino acid sequence data in a Bayesian manner, as has been applied before, such as for the definition of the mitochondrial proteome of humans ( 13 ) and of developmental stage-specific proteins in Plasmodium ( 24 , 25 ). We used a naive Bayesian classifier to combine the data.…”

DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages

“…Since PfAP2-P binds to the heterochromatic regions and its functional deletion impairs chromatin compaction, we examined whether genes normally only expressed in sporozoites are expressed in Δpfap2-p parasites 33 . Of 88 genes apparently expressed specifically in sporozoites 34 , we identified 26 to be significantly up-regulated and 4 to be significantly down-regulated in Δpfap2- 16 parasites compared with controls (Supplementary Data 1 ). A similar trend was observed at 40 h.p.i.…”