Giving malaria the slip

Malaria is an ancient disease. There are descriptions of a disease resembling malaria which date back more than 4000 years. The name malaria comes from medieval Italian: mala aria meaning “bad air”. The disease is caused by a protistan parasite called Plasmodium which is transmitted mainly by female Anopheles mosquitoes. The Plasmodium parasite invades and consumes the red blood cells of its host, which leads to symptoms including fever, anemia, and in severe cases, a coma and death. More than a million people, mostly children, die every year from malaria - this translates into one death every 30 seconds. Approximately 3 billion people in 107 countries are at risk. More than 80% of deaths from malaria occur in Africa, 15% in Asia and Eastern Europe, and only a small fraction in the Americas. The vast majority of cases occur in children under the age of five. Pregnant women are also particularly vulnerable. Precise statistics are difficult to collect because many cases occur in rural areas where people do not have access to medical care, so many cases are unreported.

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Malaria develops in two phases: a liver phase and a blood phase. When an infected mosquito bites a person to take a blood meal, cells called sporozoites in the mosquito’s saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into a human host, they infect hepatocytes (liver cells), where multiply asexually for a period of 6–15 days. Then they differentiate to yield hundreds or thousands of cells called merozoites which break out of their host’s liver cells, killing them in the process, and escape into the blood to infect red blood cells.
The malaria parasite is relatively protected from attack by immune system because for most of their life cycle they stay within the liver and blood cells and are almost invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this, Plasmodium falciparum displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, preventing infected cells from going through the general circulation and the spleen. This stickiness causes many of the symptoms of malaria. I’ll talk about a recent paper which deals with this issue later.
Several families of drugs are used to treat malaria. Chloroquine was the anti-malarial drug of choice for many years. However, resistance of Plasmodium falciparum to chloroquine has spread from Asia to Africa, making the drug ineffective against this, the most dangerous Plasmodium strain, in many regions. There are other drugs which are used for treatment and, partially, for prevention (or prophylaxis). Many drugs can be used for both purposes; larger doses are used for treatment than for prevention.
Vaccines for malaria are under development, but no effective vaccine is yet available. A team funded by the Gates Foundation recently announced results of a Phase II clinical trial of a vaccine which reduces infection risk by approximately 30%, and severity of infection by over 50%, but this vaccine will not be commercially available until at least 2010. It is hoped that the genome sequence of Plasmodium falciparum, which was completed in 2002, will provide targets for new drugs or vaccines.
As I’ve already mentioned, the most severe forms malaria are due to the Plasmodium falciparum–infected and uninfected red blood cells sticking inside vital organs. Heparan sulfate is a polysaccharide which is found on the surface of most cells. Strains of P. falciparum which use heparan sulfate as a host receptor are associated with development of severe forms of malaria. Heparin is a drug composed of the same building blocks as heparan sulfate, and was previously used in the treatment of severe malaria, but this was discontinued due to the occurrence of serious side effects such as bleeding in the brain. A group of scientists in Sweden recently showed that novel compounds derived from heparin can inhibit the merozoite stage of the life cycle infecting erythrocytes, and also blocks binding of infected red blood cells to tissues by up to 80%, so combating the most serious symptoms of malaria (Vogt AM, et al. Release of sequestered malaria parasites upon injection of a glycosaminoglycan. PLoS Pathogens 2006 2 (9)).
With no vaccine on the immediate horizon, we need all the tools we can get in our arsenal against this killer disease.