MRC National Institute for Medical Research, London
Science for Health
What controls egress of the malaria parasite from infected red blood cells?
10 May 2013
NIMR scientists have identified components of a signalling pathway that leads to release of the malaria pathogen from parasitised red blood cells. The research is published in PLOS Pathogens.
Around half of the world’s population is at risk of infection with protozoan parasites of the genus Plasmodium, the causative agent of malaria. The parasite invades erythrocytes, where it divides within a membrane-bound compartment called a parasitophorous vacuole (PV). Each infected erythrocyte then ruptures, allowing egress of daughter merozoites which rapidly invade fresh erythrocytes. Repeated cycles of intraerythrocytic replication and egress lead to a gradually increasing parasitaemia which eventually results in clinical disease. This varies in severity depending upon the Plasmodium species, but in the most virulent form of malaria, caused by Plasmodium falciparum, initial febrile episodes can quickly lead to severe pathology including anaemia, hypoglycaemia, respiratory distress, hypoxia, coma, and other complications that are often fatal.
Parasite egress from the infected erythrocyte is a rapid, parasite-driven and temporally highly regulated process. Egress is known to be preceded by the discharge of a subtilisin-like protease called SUB1 from specialised secretory organelles of the still intracellular merozoite. Upon its release into the PV lumen, SUB1 precisely cleaves a number of merozoite surface and PV proteins, initiating a process that leads to egress. In efforts to understand how egress is controlled, Christine Collins and Fiona Hackett in the laboratory of Mike Blackman (pictured) in NIMR’s Division of Parasitology, collaborated with David Baker’s group at the London School of Hygiene and Tropical Medicine. They found that SUB1 discharge requires the activity of another parasite enzyme called protein kinase G (PKG), which is in turn activated by a small signalling molecule called cGMP. Drugs that selectively inhibit parasite PKG potently block SUB1 discharge and egress. In contrast, premature activation of PKG by a member of a class of compounds called phosphodiesterase inhibitors, which increase cGMP levels in the parasite, induces premature SUB1 release and merozoite egress. Importantly, these prematurely released merozoites are immature and so mostly non-invasive.
Our observations provide the first insights into the signals that trigger malaria parasite egress, and show that both malarial PKG and parasite phosphodiesterases (enzymes which are validated drug targets in humans) are potential targets for a new class of antimalarial drugs.
Mike Blackman
Egress of P. falciparum merozoites in vitro imaged by time-lapse video microscopy.
Original article
Christine R. Collins, Fiona Hackett, Malcolm Strath, Maria Penzo, Chrislaine Withers-Martinez, David A. Baker and Michael J. Blackman
Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress
PLOS Pathogens, 9(5): e1003344. Article fulltext.
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