For malaria to be spread from person to person via a mosquito, Plasmodium parasites must undergo sexual differentiation to form gametocytes. Although an essential part of the life cycle, little is known about the production of these stages n vitro or in vivo, which complicates the development of strategies that effectively block transmission. In the previous funding period we identified a gene that is critical for gametocyte production, P. falciparum gametocyte development 1 (Pfgdv1) and the set of genes specifically expressed during early gametocytogenesis in P. falciparum (Pfge genes). Analysis of the expression profiles of these genes in vitro and in a cohort of malaria infected patients lead to th hypothesis that gametocytes are formed during each asexual cycle as part of normal development. This type of continuous gametocyte production would provide a consistent source of infectious parasites whenever a mosquito bites. However, it also has serious implications for the design of control measures and suggests that mass treatment or vaccination would be needed to eliminate the parasite. To further evaluate the initiation of gametocytogenesis in vivo, we developed a method to directly compare asexual parasitemia and gametocyte commitment in blood samples from patients. The relationship between gametocyte induction and maturation in vivo is needed to understand the factors that contribute to the production of infectious gametocytes.
Aim one will evaluate the role of patient age and hematocrit in gametocyte production, while Aims 2 and 3 will use molecular (Aim 2) and immunological (Aim 3) to understand the role of parasite exposure and immune stimulation on gametocyte commitment and maturation. This field work will complement our ongoing basic research defining the molecular basis for gametocytogenesis. Together the work will extend our understanding of the initiation and formation gametocytes that are essential for the spread of malaria. The findings should provide markers to identify gametocyte carriers before they are infectious and identify signaling pathways that could be targeted to block transmission.
New strategies are required to block the spread of malaria, which still is responsible for approximately 200 million clinical cases and the deaths of 0.6 million people each year. This goal of the project is to advance the understanding of the production of the transmission stage, the gametocyte.
|Roobsoong, Wanlapa; Maher, Steven P; Rachaphaew, Nattawan et al. (2014) A rapid sensitive, flow cytometry-based method for the detection of Plasmodium vivax-infected blood cells. Malar J 13:55|
|Joice, Regina; Nilsson, Sandra K; Montgomery, Jacqui et al. (2014) Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci Transl Med 6:244re5|
|Ikadai, Hiromi; Shaw Saliba, Kathryn; Kanzok, Stefan M et al. (2013) Transposon mutagenesis identifies genes essential for Plasmodium falciparum gametocytogenesis. Proc Natl Acad Sci U S A 110:E1676-84|
|Hobbs, Charlotte V; Tanaka, Takeshi Q; Muratova, Olga et al. (2013) HIV treatments have malaria gametocyte killing and transmission blocking activity. J Infect Dis 208:139-48|
|Eksi, Saliha; Williamson, Kim C (2011) Protein targeting to the parasitophorous vacuole membrane of Plasmodium falciparum. Eukaryot Cell 10:744-52|
|Morahan, Belinda J; Strobel, Carolyn; Hasan, Uzma et al. (2011) Functional analysis of the exported type IV HSP40 protein PfGECO in Plasmodium falciparum gametocytes. Eukaryot Cell 10:1492-503|
|Rupp, Ingrid; Sologub, Ludmilla; Williamson, Kim C et al. (2011) Malaria parasites form filamentous cell-to-cell connections during reproduction in the mosquito midgut. Cell Res 21:683-96|
|Sarda, Vanessa; Kaslow, David C; Williamson, Kim C (2009) Approaches to malaria vaccine development using the retrospectroscope. Infect Immun 77:3130-40|
|Eksi, Saliha; Suri, Amreena; Williamson, Kim C (2008) Sex- and stage-specific reporter gene expression in Plasmodium falciparum. Mol Biochem Parasitol 160:148-51|