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Malaria is a major threat to the health of thousands of millions of people throughout the tropics and subtropics. It causes hundreds of millions of episodes of disease and kills more than a million people a year, the majority of them children in sub-Saharan Africa.
Although four species of malaria parasite infect humans, severe disease and deaths are overwhelmingly due to a single species, Plasmodium falciparum. The development of new approaches to prevention and treatment depends on understanding exactly how the malaria parasite interacts with the human host and causes its damage.
In the body
Malaria parasites are transmitted to humans by the bite of anopheline mosquitoes. After injection, the parasites (at this stage known as sporozoites) circulate for only a few minutes in the blood before finding their way into the host's liver cells. Here, they divide rapidly over the next week or so, a single parasite giving rise in that time to around 30 000 daughter parasites (or merozoites). During this period of frenetic division the host remains completely well.
After a week or so, the now distended liver cell bursts open, releasing the merozoites into the blood stream, where they can only survive if they rapidly attach to and enter host red blood cells. Now the parasite is in a protected environment, shielded from detection or attack by the host's immune system. Inside the red blood cell, the parasite again grows and divides – this time forming up to 32 daughter merozoites. After around 48 hours, the host red blood cell bursts releasing merozoites into the blood to repeat the whole cycle.
This repeated cycling of growth, release and reinvasion leads to an exponential explosion of parasites in the blood – unchecked the progeny from a single parasite in the liver could lead to the destruction of all the host's red blood cells within 12 and 14 days.
Interactive: The life cycle of the malaria parasite
This exponential growth and destruction of red blood cells contributes to anaemia, one of the characteristic problems of Plasmodium falciparum malaria. When this develops rapidly, the inability to deliver sufficient oxygen to the body's vital organs is itself enough to explain many of the features of disease and to lead to the death of the host.
Two other aspects of the interactions between the host and the parasite also play key roles in leading to severe disease and death. The first is the host's immune response to the growing parasite. Although relatively protected while in the red blood cell, the parasite becomes detectable whenever it bursts out of red cells, releasing its own toxins and host cellular debris into the blood stream.
This initiates a barrage of responses from the host, including the mobilisation of protective cells and the release of chemical agents, known as cytokines, which both regulate the host's response and, in some cases, kill the parasites directly.
Any blunderbuss sort of response is difficult to control, and the cytokines that can kill parasites may also cause damage to host cells if present in excess. This is a precarious balance: too limited a response may allow the parasite to kill the host; too aggressive a response may itself kill the host. There is now clear evidence that, in some individuals, an excessive host response plays a role in the development of severe disease.
The other key aspect of the host–parasite interaction is the phenomenon of 'sequestration' or 'withdrawal' of infected red blood cells into small blood vessels of the body. While red blood cells containing young parasites can be found in the peripheral blood – and can readily be seen in blood samples taken from patients with falciparum malaria – the larger, more mature dividing parasites appear to be absent.
Instead, they are found in large numbers lining small blood vessels in many tissues of the body. The infected cell does not come to rest passively in such vessels: the parasite inserts molecules into the red blood cell surface that hook onto host receptor molecules found on the lining of blood vessels.
Quite why the mature stages of the parasite should be withdrawn is not clear. The presumption is that there is some advantage to the parasite, either by protecting it from passing through the spleen, where infected red blood cells might be recognised and removed, or by providing optimum conditions for the parasite to grow.
Whatever the case, the packing of the small blood vessels compromises blood flow and delivery of oxygen to tissues, and the tissues become damaged due to lack of oxygen.
In part 2 of Malaria and the human body, Kevin Marsh examines clinical problems, prevention and treatment
Professor Kevin Marsh is Director of the Wellcome–KEMRI-Wellcome Trust Research Programme, which is based in Kilifi and Nairobi, Kenya.
Page of 2; 2/9/04
[WTD023879] Malaria and the human body, part 1: Danger cycle.doc