Researchers in Australia have discovered a new way to prevent the deadliest malaria parasite –Plasmodium falciparum – from spreading infection.
Image Credit: Christoph Burgstedt / Shutterstock.com
Using small molecule inhibitors developed at the Walter and Eliza Hall Institute, the researchers stopped the parasite from completing the "transmission stage" of its life cycle. Blocking this transmission stage is vital for developing preventative therapies that stop the spread of disease.
As reported today in the journal Cell Reports, the inhibitors blocked an enzyme called plasmepsin V, which the parasite needs to develop gametocytes, which is the only form of the parasite that can be transmitted to mosquitoes when they take a blood meal from an infected host.
The research was led by Justin Boddey from the Walter and Eliza Hall Institute and the University of Melbourne, in collaboration with Vicky Avery from Griffith University in Queensland.
Malaria kills more than half a million people every year
More than half a million people are killed by malaria worldwide every year, and the most lethal of the parasites is P. falciparum, which accounts for 90% of infection cases.
The parasite's ability to mutate and develop resistance to therapies means new prevention and treatment strategies to target the different stages of its lifecycle (the liver stage, blood stage, and transmission stage) are urgently required.
An exciting find
Boddey says the team has made new ground in the battle to eliminate malaria because it is so important to block the parasite's transmission stage. He says it was exciting to find that plasmepsin V plays a role in malaria transmission and that the team's inhibitors could target the enzyme and block transmission to the mosquito.
"We showed that an optimal concentration of the inhibitors could kill gametocytes, and that even with a lower dose, the gametocytes made it all the way through their two-week development phase but still couldn't complete the task of transmitting infection to mosquitoes.This shows plasmepsin V is a target for transmission-blocking drugs."
Justin Boddey, University of Melbourne
What did the study involve?
Using the Walter and Eliza Hall Institute's insectary facilities, the researchers studied how gametocytes in human blood transmit malaria to the mosquito. Then, using gametocyte-specific fluorescent "tags", they showed that plasmepsin V was needed for the export of gametocyte proteins, which is essential to gametocyte transmission. They then went on to demonstrate that their small molecule inhibitors could stop this process.
The results build on previous studies, including one conducted in 2014, which found that plasmepsin V was an effective target for killing the parasite while it is in the asexual blood stage of its lifecycle. This stage of the cycle is when malaria symptoms such as fever, chills, muscle pain, and nausea, begin.
Chemical biologist Brad Sleebs, who was involved in both the current and previous plasmepsin V studies, says the enzyme was proving to be an ideal drug target because it is important for parasite's survival at different stages of its lifecycle.
"It's encouraging to observe inhibitors that target plasmepsin V are effective against both the asexual blood and sexual transmission stages of the parasite's lifecycle," says Sleebs. "Our research demonstrates that an antimalarial treatment targeting plasmepsin V has potential, not only in treatment of the disease, but also as a preventative population control measure."
"It's been a rewarding journey"
Boddey says the research is an example of how basic and translational knowledge can be established when each new study builds on the last: "It's been a rewarding journey from identifying the function of plasmepsin V, to developing inhibitors that block it and kill the malaria parasite, to now validating this enzyme's dual function as an effective blood stage and transmission-blocking drug target."
Next, the team plans to investigate the role of plasmepsin V in the remaining phase of the malaria lifecycle: the liver stage.
Boddey says the plan is to assess the enzyme as a potential multi-stage drug target for treating and preventing malaria, and to understand the unique biology occurring during liver infection. "We are also collaborating with Merck and the Wellcome Trust to develop drugs targeting plasmepsin V in multiple parasite species," he concludes.
Malaria under arrest: New drug target prevents deadly transmission. Eurekalert. Available from: https://www.eurekalert.org/emb_releases/2019-12/waeh-mua121519.php