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Malaria Gametocytogenesis Molecular & Biochemical Parasitology 172 (2010) 57–65 Contents lists available at ScienceDirect Molecular & Biochemical Parasitology Review Malaria gametocytogenesis David A. Baker ∗ Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK article info abstract Article history: Male and female gametocytes are the components of the malaria parasite life cycle which are taken Received 22 January 2010 up from an infected host bloodstream by mosquitoes and thus mediate disease transmission. These Received in revised form 29 March 2010 gamete precursors are morphologically and functionally quite distinct from their asexual blood stage Accepted 30 March 2010 counterparts and this is reflected in their distinct patterns of gene expression, cellular development and Available online 8 April 2010 metabolism. Recent transcriptome, proteome and reverse genetic studies have added valuable informa- tion to that obtained from traditional studies. However, we still have no answer to the fundamental Keywords: question regarding sexual development: ‘what triggers gametocytogenesis’? In the current climate of Malaria Plasmodium eradication/elimination, tackling transmission by killing gametocytes has an important place on the Gametocyte agenda because most antimalarial drugs, whilst killing asexual blood stage parasites, have no effect on Parasite the transmissible stages. Drug © 2010 Elsevier B.V. Open access under CC BY license. Differentiation Contents 1. Introduction .......................................................................................................................................... 57 2. The distinct morphology of gametocytes compared to the asexual blood stages is reflected in their unique pattern of gene expression........ 58 3. Gametocyte metabolism ............................................................................................................................. 58 3.1. Nucleic acid synthesis ........................................................................................................................ 58 3.2. Carbohydrate metabolism and energy production .......................................................................................... 59 3.3. The mitochondrion and apicoplast ........................................................................................................... 59 4. What causes gametocytogenesis? ................................................................................................................... 59 5. P. falciparum isolates vary in their capacity to produce gametocytes in the laboratory ............................................................ 60 6. Sex ratios ............................................................................................................................................. 61 7. Gametocyte proteins with a subsequent role in fertilisation ....................................................................................... 61 8. Cytoadherence and sequestration ................................................................................................................... 62 9. Drugs that affect gametocyte development and reduce transmission .............................................................................. 62 10. Concluding remarks ................................................................................................................................ 63 Acknowledgements .................................................................................................................................. 63 References ........................................................................................................................................... 63 1. Introduction parasites within the red blood cells of a human host leads to the pathology and symptoms of malaria. The malaria parasite life cycle Malaria is caused by protozoa of the genus Plasmodium; these also comprises a phase of sexual reproduction which takes place are apicomplexan parasites and are part of the alveolate group- in the mosquito vector, but the actual switch to sexual develop- ing [1]. As well as other animal pathogens such as Toxoplasma, ment occurs in the vertebrate host, with the formation of male Crytptosporidium, Theileria and Eimeria, alveolates also comprise and female gamete precursors (gametocytes), and is a prerequi- free living ciliate protozoa such as Paramecium and Tetrahy- site for transmission of disease [2]. This review will focus on our mena and also the dinoflagellates. Asexual proliferation of malaria current knowledge of the biology of gametocytes and their devel- opment, and will highlight how the parasite genome sequence and post-genomic approaches have advanced our understanding ∗ Tel.: +44 (0)20 7927 2664; fax: +44 (0)20 7636 8739. of this important life cycle stage. The majority of the information E-mail address: [email protected]. has been derived from research carried out on the major human 0166-6851© 2010 Elsevier B.V. Open access under CC BY license. doi:10.1016/j.molbiopara.2010.03.019 58 D.A. Baker / Molecular & Biochemical Parasitology 172 (2010) 57–65 pathogen Plasmodium falciparum where the blood stages can read- which determine the characteristic shape of gametocytes. The ily be cultured in vitro [3], but also the rodent malaria parasite highly distinct morphology and, to some extent, the extended Plasmodium berghei which is a genetically more amenable system period of development made it obvious that P. falciparum game- and provides an important in vivo model [4]. It is encouraging that tocytes would express a large number of proteins specific to this advances in our knowledge are being made continuously, though stage of development. It also became clear that sexual stage spe- consequently a review can provide a snapshot at best. The nature cific promoters were present that regulate the precise temporal of reverse genetic techniques currently applicable to Plasmodium expression of genes. For example, in one of the first studies to exam- provided a window of opportunity to advance the study of sexual ine this issue, transfection of Plasmodium gallinaceum with reporter stage genes and has facilitated recent progress. The recent funding constructs containing a segment of 5 UTR of the Pfs16 and Pfs25 injection to support malaria elimination/eradication efforts and the genes upstream of GFP was sufficient to direct expression in a sex- resulting growing recognition of the importance of tackling trans- ual stage specific manner, and also governed appropriate temporal mission [5,6] will provide an opportunity to further increase our expression [19]. understanding of the biology of these fascinating life cycle stages. Examination of the P. falciparum proteome detected more than 900 proteins in gametocytes; 315 of these were found exclusively in gametocytes. More than 600 proteins were found in gametes 2. The distinct morphology of gametocytes compared to and 97 of these were gamete-specific [20]. Around 250–300 genes the asexual blood stages is reflected in their unique pattern specifically upregulated at the mRNA level during P. falciparum of gene expression gametocyte development have been detected by transcriptome analysis [11,21]. A sex-specific proteome study in P. berghei has Though a large proportion of the work on Plasmodium gameto- shown that a large proportion of the 5–600 proteins are expressed cytes has been carried out on P. falciparum, the extended period exclusively in either male or female gametocytes and relatively (8–12 days) of development (see [6] for review) is unique to this few are expressed in both, reflecting the individual roles of the species (and the closely related primate malaria parasite Plasmod- two sexes. This study utilised the fact that gametocytes have sex- ium reichenowi [2]). Therefore some of the findings may not be specific promoters and two of these were used to drive expression relevant to other malaria species. P. falciparum gametocyte devel- of distinct fluorescent tags allowing cell sorting [22]. Proteins iden- opment can be conveniently divided into five morphologically tified in males included those that will subsequently be involved recognisable stages (I–V) according to a widely used classifica- in axoneme formation and motility, but also DNA replication that tion system [7]. This system documents the distinctive changes in follows activation. The distribution of mitochondrial enzymes and appearance that occur following invasion of a red cell by a sex- proteins involved in protein synthesis were biased towards female ually committed merozoite. After the (sexually committed) ring gamete preparations. Sexual dimorphism is morphologically most stage, the gametocyte grows and elongates to gradually occupy the apparent from stage IV onwards in P. falciparum and this stage majority of the host red cell. Stage I gametocytes (up to ∼40 h post- is characterised by an elongated shape with both ends pointed. invasion) are difficult to distinguish from young trophozoites in a The female gametocyte or ‘macrogametocyte’ is characterised by Giemsa-stained blood film, but are roundish and a pointed end and a relatively small nucleus (with a nucleolus) and concentrated pig- distinctive pigment pattern may be visible. Specific antibodies to ment pattern; by contrast the nucleus is larger (apparently lacking a early gametocyte markers using IFA are required to be 100% certain nucleolus) and the pigment more
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