An enzyme of the malaria parasite Plasmodium that's important in
the blood stage of the disease also plays a key role in the
asymptomatic liver phase, making it a good target for new
drugs.
The enzyme, called SUB1, has previously been implicated in
releasing the parasite from infected red blood cells. Now,
scientists at the Medical Research Council's National Institute for
Medical Research (NIMR; now part of the Francis Crick
Institute) and the Wellcome Trust Sanger Institute have
discovered it's also involved in the liver phase of disease.
When a person is bitten by a mosquito infected with Plasmodium,
forms of the parasite called sporozoites are released into their
bloodstream, where they travel to the liver and invade liver cells.
Each sporozoite then replicates many times, producing thousands of
parasite cells called merozoites. These are released back into the
host's bloodstream to start the blood stage of the life cycle,
which is responsible for all the clinical symptoms of the
disease.
Professor Mike Blackman of the NIMR explained: "Growth of
malarial liver stages represents a massive expansion of the
transmitted parasite infection and is crucial for disease
progression. In this study, we have shown that a parasite enzyme
previously thought to play a role primarily in development of blood
stages is also indispensable for development in the liver."
The scientists used a technique called 'recombineering'
alongside a gene deletion strategy to investigate the effect of
completely disabling the SUB1 gene in the parasite's liver
stages.
They found that SUB1 is not required for the early stages of
growth inside liver cells, but is essential for development of
liver stage schizonts (the lifecycle stage in between sporozoites
and merozoites), as well as for the production of mature liver
merozoites.
Dr Catherine Suarez, also of NIMR, said: "Our results show that,
as well as potentially preventing growth of blood-stage parasites
that cause disease, inhibitors of SUB1 could be used in
preventative approaches to control the clinically silent liver
stage of the malaria parasite life cycle."
Professor Blackman added: "We know from previous work that SUB1
in the malaria parasite is a 'druggable' enzyme; that is, it can be
accessed and inhibited by small compounds that have potential to be
developed into drugs. Our new findings raise the possibility of
developing drugs that block the development of a malarial infection
well before it progresses to the point where it begins to cause
clinical disease."
The paper, The malarial serine protease SUB1 plays an essential role in
parasite liver stage development, is published in PLOS
Pathogens.