Abstract
Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes. To better understand how gametocytes differ from asexual blood-stage parasites, we performed a systematic analysis of available ‘omics data for P. falciparum and other Plasmodium species. 18 transcriptomic and proteomic data sets were evaluated for the presence of curated “gold standards” of 41 gametocyte-specific versus 46 non-gametocyte genes and integrated using Bayesian probabilities, resulting in gametocyte-specificity scores for all P. falciparum genes. To illustrate the utility of the gametocyte score, we explored newly predicted gametocyte-specific genes as potential biomarkers of gametocyte carriage and exposure. We analyzed the humoral immune response in field samples against 30 novel gametocyte-specific antigens and found five antigens to be differentially recognized by gametocyte carriers as compared to malaria-infected individuals without detectable gametocytes. We also validated the gametocyte-specificity of 15 identified gametocyte transcripts on culture material and samples from naturally infected individuals, resulting in eight transcripts that were >1000-fold higher expressed in gametocytes compared to asexual parasites and whose transcript abundance allowed gametocyte detection in naturally infected individuals. Our integrated genome-wide gametocyte-specificity scores provide a comprehensive resource to identify targets and monitor P. falciparum gametocytemia.
Highlights
Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes
Since gametocyte biology differs between Plasmodium species, scores were calculated for the total set of Plasmodium studies and for Plasmodium falciparum (Pf) only
Unsupervised clustering of genes based on peptide counts or mRNA expression resulted in grouping according to data acquisition method rather than parasite stage (Fig. 1), illustrating the necessity of a supervised approach to discriminate between gametocyte-specific and non-gametocyte genes
Summary
Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes. A key aspect of the methodology is that it takes into account the predictive power of each contributing data set: it assigns weights to data sets based on their ability to distinguish gold standard lists of gametocyte and asexual proteins These we have constructed using existing literature where life-stage specificity was confirmed using classical “non-omics” approaches (e.g. protein detection in immunofluorescence-assays, functional/genetic studies), followed by expert curation. We confirmed gametocyte-specificity for a selection of gametocyte-specific transcripts using culture material from geographically distinct Pf strains and samples from naturally infected malaria patients
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