Shutting the gate on the malaria parasite

Blocking a gateway the malaria parasite uses to access proteins important to its survival provides a potentially new target for the development of antimalarial drugs.

Malaria is one of the most common parasitic infections in the world. Spread via mosquitoes, its most lethal form is caused by the parasite Plasmodium falciparum. It is estimated 250 million new cases of malaria are diagnosed each year with more than half a million people, mainly children, dying from the disease.

The malaria parasite survives in the body by existing inside red blood cells. Before establishing itself, the parasite modifies the red blood cell by sending several hundred of its own proteins into the cytosol of its host cell. This protein export is essential for parasite survival as it enables the parasite to grow and thrive by attracting more nutrients.

The parasite proteins also facilitate red blood cells sticking to walls of blood vessels, thus evading destruction by the immune system.

Using two different techniques, scientists from Burnet Institute and Deakin University in Victoria deciphered how the parasite traffics these proteins beyond its encasing vacuole.

The researchers identified that the trafficking machinery is a single protein complex called PTEX located in the vacuole membrane of the parasite.

Powered by ATP, the PTEX complex comprises heat shock protein 101, a novel protein called PTEX150 and a known membrane-associated parasite protein, exported protein 2 (EXP2), which is likely to form the potential channel. Two other proteins, a new protein PTEX88 and thioredoxin 2, were also identified as PTEX components.

The researchers then demonstrated that if the function of the gateway is altered the proteins can no longer get into the red blood cells and the parasites starve.

“This is a major advance in the quest for new malaria drugs. If we can discover a drug that blocks the protein complex that comprises this gateway, you can effectively block the functioning of several hundred proteins,” Burnet Institute Director and CEO, and co-author of the paper, Professor Brendan Crabb said.

New treatment avenues are needed to control malaria because the parasite is becoming increasingly resistant to available drugs.

“We knew that this gateway existed but did not have solid evidence to show that it was the only pathway for hundreds of parasite proteins to access the host cell, until now,” said Associate Professor Tania De Koning-Ward from Deakin University Medical School.

“Through the Deakin labs, and those at the Burnet Institute, we took genetic approaches to block different components of the gateway. We each found that it was possible to stop the parasite proteins from being exported, which proved lethal to the parasite. Hence, this work also validated components of the gateway as antimalaria drug targets.

“We are now looking to better understand how the gateway is established, which will help with drug development in the future.”

The study was published in Nature.