Scientists have identified components of a signalling pathway that leads to release of the malaria parasite from infected human red blood cells. The work, led by Mike Blackman at the MRC's National Institute for Medical Research (now part of the Francis Crick Institute), may lead to new approaches to treating this devastating disease.
Malaria is caused by six species of protozoan parasites called Plasmodium, which are spread to people through the bites of infected mosquitoes. Around half of the world's population live in regions where they are at risk of infection by these parasites.
When passed to a human host by a mosquito, the malaria parasite invades a red blood cell, where it divides. Each infected red blood cell then ruptures, allowing around 16 new parasites, in an asexually reproducing form known as merozoites, to leave the red blood cell and invade fresh ones.
This process is known as replication and egress, and repeated cycles lead to a gradually increasing level of parasites in the blood, eventually resulting in clinical disease. The severity of the disease depends on the Plasmodium species a person is infected with; the most dangerous form is caused by Plasmodium falciparum.
Dr Blackman explained: "We have been interested for several years in understanding how the parasite ruptures its host red blood cell, with a long-term aim of using our knowledge in the development of drugs that prevent egress. Such drugs would trap the merozoites inside the host cell, preventing further parasite replication and so stalling progression of the disease."
Egress of the parasite from an infected red blood cell is a highly regulated process that is driven by the malaria parasite itself. The MRC team collaborated with David Baker at the London School of Hygiene and Tropical Medicine to learn more about exactly how the process is regulated.
In previous work in 2007, the researchers showed that, just before egress, the merozoites secrete an enzyme called a protease which somehow triggers the events that lead to rupture of the host red blood cell. In the current study, they wanted to understand how the release of this protease, called SUB1, was controlled. This is important because the timing of egress is known to be critical; it must not occur before the developing merozoites are fully mature.
The team discovered that release of SUB1 requires the activity of another parasite enzyme called protein kinase G (PKG), which is in turn activated by a small signalling molecule called cGMP. They showed that drugs that inhibit PKG blocked SUB1 release and egress. In addition, premature activation of PKG by another drug that increased cGMP levels in the parasite caused premature SUB1 release and egress. In the latter case, the prematurely released merozoites were immature and so could not effectively invade new red blood cells.
Dr Blackman said: "Our work has shown that cGMP is a key regulator of malarial egress, giving us the first clues as to the molecular signals that tell the parasite when to escape its host red blood cell. Drugs that target PKG, or that reduce cGMP levels, should block egress.
"In addition, our work shows that drugs that selectively enhance cGMP levels in the parasite trigger premature release of immature, non-invasive parasites which is similarly likely to prevent disease progression. Of particular importance, several existing drugs already licensed for use in humans affect cGMP levels, and so our hope is that we can now exploit knowledge of those drugs to develop new approaches to antimalarial therapies."
The paper, Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress, is published in PLOS Pathogens.
Time-lapse video microscopy of malaria parasites (merozoite stage) leaving host cells. Made by Michael Blackman, Division of Parasitology, NIMR, London.