Potential new drug target for tackling malaria

A research team at the University of Adelaide have used a novel image analysis method to help understand how a key protein controls malaria parasite entry into host red blood cells.

Published in Nature Communications, the finding identifies a promising new target for the development of drugs to treat or prevent malaria.

To cause disease, the malaria parasite, Plasmodiun falciparum, has to live inside our oxygen-carrying red blood cells. A research team lead by Dr Danny Wilson at the University of Adelaide, identified a new protein, that they call CERLI1, in the invasive stage of the parasite. Using confocal microscopy at our University of Adelaide facility, Adelaide Microscopy, and super-resolution microscopy performed elsewhere, along with genetic and image analysis techniques, the researchers have found that CERLI1 is essential for parasites to enter the host blood cells.

“Confocal microscopy was used to study the 3D spatial organisation of this newly identified malaria protein in an invasive form of the parasite. It showed us that CERLI1 is closely associated with the parasite organelles crucial for the release of a whole range of additional proteins called invasins that allow the parasite to invade red blood cells. Removing CERLI1 from the parasites prevented them from invading the host cells.” said microscopist Dr Sonja Frölich.

Using the confocal microscope Ben Liffner and Dr Frölich generated a 3D volume showing the protein’s location in hundreds of parallel horizontal slices through the sample. This data was then processed using a novel quantitative analytical approach that allowed the researchers to measure the closeness of CERLI1’s association with other known proteins inside the organelles of the malarial parasite.

Confocal images showing the close association of the CERLI1 protein (green) with the invasion organelles (red) inside a malaria parasite.

“Two hundred million people are infected with mosquito-transmitted malaria parasites every year leading to more than 400,000 deaths, mainly in children under five years of age,” says Dr Danny Wilson the Laboratory Head of Malaria Biology at the University of Adelaide.

“Our most effective malaria control strategies – drugs to treat sick people and insecticides to kill the mosquito vector – are at risk due to spreading parasite and mosquito resistance. Understanding the biology that is essential for the survival of these widespread human pathogens is essential if we are to identify new intervention strategies to combat malaria.”

“When CERLI1 no longer functions, the malaria parasites cannot invade red blood cells and the disease-causing parasite dies,” says Dr Wilson. “This marks the protein as a good potential target for future drug development.”

“Because malaria parasite invasion into red blood cells is essential for disease and requires the coordinated activity of a large number of unique proteins, blocking invasion using drugs or vaccines that target unique invasion proteins remains an important strategy for developing new therapeutics.”

CERLI1 is one of only a handful of proteins identified that acts in the way it does to allow invasion protein to interact with the host cell, making it an attractive target to develop drugs that prevent red blood cell invasion.

The researchers say that these findings may have wide biological and therapeutic implications for other human and animal disease-causing parasites.

This research was carried out primarily at the Research Centre for Infectious Diseases of the University of Adelaide as part of an international collaboration with the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany and the University of Melbourne.