Understand thine enemy

The first stage of malaria infection begins when an infected female Anopheles mosquito partakes of a human blood meal. In doing so, it injects malarial sporozoite forms from its saliva into the host bloodstream. The sporozoites rapidly migrate to the liver where they infect hepatocytes within 30 minutes of the bite.

There they hang out and multiply for six to 15 days, before sneaking out of the liver as merozoites wrapped in liver cell membranes and re-entering the bloodstream to invade red blood cells.

The merozoites mature and replicate within the erythrocytes, periodically bursting out in lots of 16-32 to invade fresh red blood cells in a process that takes less than a minute. Several such amplification cycles of infection and parasite escape occur, correlating with the classical waves of fever symptoms.

In fact, this blood stage of infection accounts for all the morbidity and mortality associated with malaria. In the absence of drug treatment, infected individuals can die quite quickly from cerebral malaria. Others may die later from overwhelming anemia or organ failure.

In surviving individuals, the parasites may further differentiate into a form that is infectious for mosquitoes, thus permitting the parasite life cycle to continue.

This invasion and occupation of the human erythrocyte by malarial merozoites is key to the disease progression and has been a major focus of Cowman's research over many years. Cowman wants to understand exactly how the parasite invades and his group has published key findings on the process.

"We know that Plasmodium uses a range of ligands to bind and activate invasion of the red blood cell it infects, and that different strains of parasite express different ligands," he says. "Basically, this diversity is one of the parasite's ways of getting around the host immune responses.

"In addition, the malaria parasite has selected polymorphisms on the red blood cell surface over thousands of years, and developed mechanisms to get around those polymorphisms to invade."

The process is obligatory and parasite-specific, making the proteins involved potential targets for novel treatments.

The data generated by this fundamental research on erythrocyte invasion by the parasite feeds directly into identifying potential vaccine candidates. Cowman, together with his colleague Dr Brendan Crabb, received funding recently from the Bill and Melinda Gates Foundation to compile the best vaccine candidates to target the red blood cell/parasite interactions.

"The biggest obstacle to such a vaccine working is variation - that is, antigenic diversity within the parasite. There is a huge amount of selective pressure on the parasite to generate this diversity to outsmart the host defences and continue its life cycle. "This parasite is a master burglar, as different forms of the malarial parasite have different keys to locks on the red blood cell surface and can use these separately and in different combinations.

"A successful vaccine probably needs to block all those entries. We think we have now identified all these pathways and are close to identifying the best protein and domain combinations to use in a potential vaccine."