Plasmodium falciparum Gametocyte Development 1 (Pfgdv1) and Gametocytogenesis Early Gene Identification and Commitment to Sexual Development

Abstract

Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut. Although essential for the spread of malaria through the population, little is known about the initiation of gametocytogenesis in vitro or in vivo. Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparum gametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation. Transcriptional analysis of Pfgdv1 negative and positive parasite lines identified a set of gametocytogenesis early genes (Pfge) that were significantly down-regulated (>10 fold) in the absence of Pfgdv1 and expression was restored after Pfgdv1 complementation. Progressive accumulation of Pfge transcripts during successive rounds of asexual replication in synchronized cultures suggests that gametocytes are induced continuously during asexual growth. Comparison of Pfge gene transcriptional profiles in patient samples divided the genes into two groups differing in their expression in mature circulating gametocytes and providing candidates to evaluate gametocyte induction and maturation separately in vivo. The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria.

A Plasmodium falciparum Histone Deacetylase Regulates Antigenic Variation and Gametocyte Conversion

“…In each asexual cycle of the P. falciparum blood-stage, a small subpopulation of parasites converts to the sexual gametocyte form required for transmission to the mosquito vector. Recently, genetic determinants for sexual differentiation have been identified in P. falciparum (Eksi et al, 2012; Ikadai et al, 2013; Rovira-Graells et al, 2012; Silvestrini et al, 2010; Young et al, 2005). However, the molecular basis for the frequency of switching from the asexual cycle to sexual development remains obscure.…”

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

“…For example, gametocyte maturation and gametocytogenesis are accompanied by the coordinated expression of adhesive proteins, such as the epidermal growth factor domain-containing proteins P. falciparum s25 (Pfs25) and P. falciparum s28 (Pfs28), the 6-Cys proteins P. falciparum s230 (Pfs230) and P. falciparum s48/45 (Pfs48/45), and the LCCL domain-containing P. falciparum CCp (PfCCp) proteins (20)(21)(22)(23). Recent work has also identified the P. falciparum gametocyte development 1 (Pfgdv1) gene as being critical for gametocyte production (24). In addition, transcriptomic data demonstrate significant changes in a subset of genes immediately following malaria parasite transmission to the mosquito (17).…”

Sex in Plasmodium falciparum: Silence Play between GDV1 and HP1

“…In 2012, Eksi et al . showed that gametocyte development 1 (GDV1), a perinuclear Plasmodium falciparum protein, plays a role in gametocytogenesis [1]. GDV1 overexpression enhanced gametocyte formation, whereas gdv1 -deleted parasite lines were gametocyte deficient.…”

“…These data further substantiate the earlier finding by Eksi et al . [1] that overexpression of Pfgdv1 modulates gametocytogenesis in a dynamic fashion.…”

“…Interestingly, there is no syntenic GDV1 locus in rodent malaria genomes, including P. berghei [1], suggesting that this mechanism is not conserved in all species. Alternatively, another gene with similar function may fulfil this role.…”