Malaria is a pernicious public health problem in many areas of the world. Sub-Saharan Africa, where cases recorded represent over 90% of the world total, is particularly badly hit. Modelling by IRD scientists has revealed a core feature in the life-cycle of Plasmodium falciparum, the parasite responsible for the disease. Its gametocytes, the pre-gamete sexual forms, aggregate in clusters in human blood capillaries and, once ingested, keep this form until they reach the ideal breeding ground the mosquito's stomach provides. Conditions there favour encounters, and hence binding, between male and female gametocytes, thereby enhancing the parasite's fertilization and reproduction capacity. Investigation of this behaviour should yield important information on both the parasite's transmission to humans and on the way the disease develops.
Malaria, which infects 600 million people in the world and leads annually to 2 million deaths, is the most widespread of infectious diseases. The pathological agent is a microscopic parasite of the Plasmodium genus which develops inside the host's erythrocytes. Plasmodia go through a series of asexual reproduction cycles before a transition takes place from asexual stages to production of sexual cells, the gametocytes or pre-gametes, in the host blood. The females of Anopheles, the mosquito vector, ingest blood and gametocytes during a nocturnal feed on human skin. The meal reaches the mosquito's stomach where Plasmodium sexual reproduction takes place. An encounter and subsequent binding between a male and a female gametocyte produces a zygote which will give rise to infectious forms. These migrate up to the mosquito salivary glands. From there they are transmitted to humans during a second blood meal.
Experimental gametocyte counts in the blood ingested by mosquitoes that had bitten volunteers naturally infected with Plasmodium falciparum showed that these sexual forms are overdispersed, in other words they have a heterogeneous distribution in the mosquito stomach. Their numbers vary between the different blood meals taken on the same volunteer, a feature previously observed in the case of large parasites (macroparasites), such as microfilariae (250 microns).
The IRD team is researching Plasmodium biology and the modes of transmission from the vector to humans and from humans to the vector. They used a computerized simulation model (the individual based model) of gametocyte behaviour in human blood circulation and at the moment of ingestion by the mosquitoes, aiming to find an explanation for this heterogeneity and its role in the parasite's reproduction.
In the microfilariae, nematode agents of filariases, heterogeneity in the number of parasites ingested by the mosquitoes results from queues of varying lengths they form in the capillaries. Thus a similar aggregation event might occur in Plasmodium gametocytes, even if their very small size (10 microns) theoretically predestine them for a homogeneous distribution in the mosquito stomach. Simulations tested this hypothesis, each assuming different quantities of circulating gametocytes. They showed that the heterogeneous distribution of gametocytes ingested by the mosquito is no chance feature but is density-dependent, increasing with the gametocyte density. This heterogeneity could result from gametocyte togetherness, or aggregation, in the blood capillaries, the clusters so formed persisting in the mosquito stomach where sexual reproduction takes place. Field experiments conducted in Senegal, then others in Cameroon, on blood ingested by mosquitoes from naturally infected volunteers have confirmed these results, thus validating the model the research team adopted.
Comparison of the behaviour of free and clustered gametocytes has illuminated an essential life-cycle characteristic of Plasmodium, the most extensively studied malaria parasite. Aggregation is a means of optimizing the zygote (fertilized ova) production, which results from the encounter and binding between two gametocytes of opposite sex, and therefore of enhancing the production of infectious forms and the parasite's reproduction rate. Bound in the human host's peripheral capillaries, male and female gametocytes ingested by a mosquito increase the likelihood of their meeting inside the propitious breeding ground the fly's stomach provides. The gametocytes differentiate into gametes that possess no particular means of attraction, so this lover's ritual of clustering is a sophisticated parasite reproduction strategy which compensates for its gametes' lack of attraction mechanism. Further research is planned, with three main objectives: refining the gametocyte behaviour model; finding out the triggering mechanism behind the cell binding events, well known in the asexual forms which cause cerebral malaria; and identifying the factors that influence the cluster formation.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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