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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.
Dangerous Times
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
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The life cycle of the malaria parasite in the human body is intimately tied to the clinical problems it produces (see part 1 of Malaria and the human body). These clinical problems can be predicted from these three main aspects of host–parasite interaction:
In most cases, malaria is a febrile illness with a wide range of symptoms that include headache, rigors, muscle pains, lassitude, and cough – most of which probably reflect activation of cytokines.
The episode is usually limited, either by the host's response or by treatment, but in a proportion of cases the disease progresses to become severe and life threatening.
Although complex, the clinical picture of severe malaria is dominated by three main problems: anaemia, respiratory distress and coma, and these can be seen as resulting from the interaction of the three main components of the host–parasite interaction discussed above.
Thus, severe anaemia may result from rapid parasite growth and red blood cell destruction (although the removal of uninfected red blood cells by an overenthusiastic immune system, and the suppression of the bone marrow response by cytokines, also play a role).
Reduced oxygen delivery to tissues caused by a combination of small vessel obstruction, and exacerbated by reduced oxygen-carrying capacity due to anaemia, leads to a profound metabolic acidosis (where the blood becomes too acidic). This in turn leads to respiratory distress, a compensatory mechanism by which the patient breathes harder to try to 'blow off' carbon dioxide to reduce the acidity.
The most well known and feared manifestation of severe malaria is cerebral malaria, in which the patient goes into coma and often has convulsions.
In some cases, coma seems to be the body's response to overwhelming metabolic disturbance, particularly the metabolic acidosis described above. But in other cases the general features described above are specifically focused in the brain, with massive packing of blood vessels by infected parasites, leading to a variety of local effects, including tissue damage, cytokine activation and other poorly understood cellular pathology.
Prevention And Treatment
The key to reducing malaria deaths is prevention of infection. Historically, emphasis was on reducing the numbers of mosquitoes by a combination of environmental hygiene and residual insecticide spraying. While still important in many settings, these approaches are often of limited use in widespread rural communities which bear the brunt of the malaria threat. Here, the current emphasis is on individual protection by sleeping under insecticide-impregnated bednets, an approach demonstrated to have major effects in reducing childhood mortality.
The prevention of mosquito biting is only ever partial, however, and in most circumstances the major barrier between malaria infection and death is the early use of antimalarial drugs as soon as the patient has fever. Here the major problem is the development of resistance to chloroquine, a cheap and effective drug.
There is a desperate need for the development of new, safe affordable antimalarials. Once severe malaria has developed, antimalarial drugs still have a role but just as important is rapid management of the problems discussed above: blood transfusion for anaemia, fluid therapy to correct acidosis and the treatment of convulsions to limit subsequent brain damage.
While malaria has been eradicated from some areas of the world, these were essentially regions where the balance between transmission and control was already precarious. There is no prospect of eradication with currently available measures in the core areas of malaria's range, where the dynamics of transmission massively favour the parasite.
In sub-Saharan Africa in particular, there will continue to be a race between the development of new approaches to control and the parasite's ability to evade them.
Currently the parasite has the upper hand. Central to attempts to reverse this are the search for novel antimalarial drugs and the development of vaccines.
But malaria is complex and successful, and all the easy options have been exhausted.
New approaches depend critically on developing a holistic view which integrates our understanding of malaria, from the most basic realities of life for those who are its victims to the most fundamental aspects of the parasite's biology, and it is here that the information from the genome project will play a critical role.
Professor Kevin Marsh is Director of the KEMRI-Wellcome Trust Research Programme, which is based in Kilifi and Nairobi, Kenya.
Page of 2; 2/9/04
[WTD023880] Malaria and the human body, part 2: Tackling illness.doc
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Page of 2; 2/9/04
[WTD023879] Malaria and the human body, part 1: Danger cycle.doc
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