The Forever War: Breaking the Cycles of Despair

Visualizing the Sexual Stages of Plasmodium falciparum: Gametocytogenesis and Targeted Interventions

This animation explores the role of the gametocyte in the life cycle of Plasmodium falciparum, the causative agent of malaria, and gametocyte targeted interventions for malaria elimination and eradictation. A key strategy for eradicating malaria involves blocking the human – mosquito – human transmission of the causative parasite. The only form of the parasite that can be transmitted from a human to the mosquito vector is the mature (stage V) gametocyte. Despite its essential role in the parasite life cycle, very little is known about the gametocyte. As early as 1880, the distinct crescent shape of the mature gametocyte was observed in blood smears from malaria patients. However, the cellular and molecular basis underlying the development of this transmission stage remains poorly understood.

Gametocytogenesis: Biology

Lifecycle and Morphology clip and narration, Part I

Malaria remains a significant global health problem with an excess of 1 million deaths per year, primarily among children under 5 years of age in Sub-Saharan Africa. The Plasmodium parasite, the causative agent of malaria, lives a complex life cycle in two evolutionarily divergent hosts, the human and the mosquito. Although Plasmodium transmission is clearly recognized as an important step in the parasite life cycle, very little is known about the sexual or “gametocyte” stages, which are the only parasite forms that can be transmitted from a human to the mosquito.

Human infection is initiated by the bite of an infected Anopheles mosquito, wherein sporozoite  stages are injected into the skin and then traffic in the bloodstream to the liver. Following liver-stage development, thousands of merozoites are released into the blood to infect red blood cells (RBCs). A subset of these asexual parasites receives a “commitment signal” that initiates sexual differentiation, or “gametocytogenesis”. Merozoites are then released from sexually committed schizont-infected RBCs, invade a new RBC and form the “gametoring” stage. Maturation, the final phase of gametocytogenesis, is initiated and the gametoring enters a cellular differentiation process divided into five developmental and morphologically discrete stages. The inner membrane complex (IMC), which is supported by the microtubule network is involved in this process, and the IMC and the microtubule network expand around the periphery; thereby influencing cell shape. During stage 4, the IMC has been stretched and completely surrounds the parasite. When the microtubule network is disassembled it results in the relaxation of the ends of the gametocyte producing the characteristic stage 5 crescent. The Plasmodium parasite has completed gametocytogenesis. Terminally differentiated stage 5 male and female parasites circulate in the peripheral blood stream and capillary venules and are easily distinguishable by light microscopy in Giemsa stained thin blood smears.

Interventions to block gametocyte persistence in the bloodstream, and transmission to mosquitoes are urgently needed, especially in the context of malaria elimination and eradication.

 Transmission Blocking Vaccines, TBV

Targeted Interventions clip and narration, Part II

Following immunization with a TBV, antibodies elicited against parasite surface antigens can either clear gametocytes in the bloodstream or, upon uptake with gametocytes into the mosquito midgut during blood feeding, prevent downstream developmental stages thereby blocking malaria transmission. Classical TBVs can target gametocyte, gamete or ookinete proteins. However, of these three stages, only gametocytes are present in the human host, and targeting gametocytes may allow for natural boosting of the vaccine. To date, the majority of candidate gametocyte surface antigens remain untested as TBV targets.

Vaccine efficacy depends on the intrinsic ability of a vaccinated individual to mount an immune response, and this is negatively impacted by the poor health and nutrition status of vaccinees in malaria endemic countries. Therefore, transmission-blocking drugs offer an alternative approach that can circumvent this hurdle.

Transmission Blocking Drugs

Targeted Interventions clip and narration, Part III

Primaquine, PQ, is the only drug currently available that is effective against stage V gametocytes. The exact mechanism is not well understood but is reported to affect parasite mitochondria. However, clinical use is limited by PQs toxicity, particularly in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is common in malaria endemic regions.

Artemisinin is an effective antimalarial but activity is limited to asexuals and stage I-III gametocytes.  Discovery of new drugs that are focused on preventing gametocyte development, killing mature stage Vs in humans or preventing gametogenesis and fertilization in the mosquito could result in significant reductions in the number of infected mosquito vectors. However, the underlying genetic and biochemical pathways driving gametocytogenesis and as a result, the number of potential druggable targets remains unknown.

StageVInfectedRBC

In the era of malaria elimination and eradication, research must be focused on breaking the cycle of malaria transmission.   To do so, we must fill the gaps in our knowledge about gametocyte developmental biology so that we can develop a multifaceted approach to saving lives and eradicating this disease.

Special Thanks:

Rhoel Dinglasan, Ph.D., M.P.H.,  at Johns Hopkins School of Public Health and The Johns Hopkins Malaria Research Institute who served as my thesis preceptor and content expert. For more information about his research, please see dinglasanlab.org.

Corinne Sandone, M.A., C.M.I.,  Associate Professor at the Johns Hopkins University School of Medicine Department of Art as Applied to Medicine who served as my faculty advisor.

Matthias Marti, Ph.D. and Sue Ka-Yee Law, Ph.D. at Harvard School of Public Health. For the generosity of their lab sharing data driven files to model the 3D stage IV and V gametocytes.

This project and animation was made to meet partial fulfillment of Master of Arts degree at the Johns Hopkins School of Medicine, Department of Art as Applied to Medicine. © 2013 Heidi Sinsel, All Rights Reserved.


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