In a significant breakthrough, researchers from the Swiss Tropical and Public Health Institute (Swiss TPH) and Griffith University’s Institute for Glycomics have unveiled a crucial aspect of how the malaria parasite infiltrates human red blood cells.

The study, recently published in Cell Reports, highlights the pivotal role of a sugar known as sialic acid in this invasive process, with far-reaching implications for malaria vaccine and drug development.

Malaria, a persistent global health menace, recorded a staggering 249 million cases and 608,000 fatalities in 2022 alone. The malaria parasite, Plasmodium falciparum stands out as the main culprit behind severe malaria cases and the majority of malaria-related deaths, inducing clinical symptoms through its multiplication within red blood cells.

While the invasion of human red blood cells by P. falciparum has long been recognised, the precise molecular targets exploited by the parasite remained elusive. Although the role of the malaria protein, cysteine-rich protective antigen (CyRPA), was acknowledged in this invasion process, its specific contribution remained unclear.

A collaborative team, spearheaded by researchers from Swiss TPH and the Institute for Glycomics, delved into the binding dynamics of CyRPA. Their investigations pinpointed sialic acid as a critical component present on the surface of red blood cells, essential for the invasion process. Their findings mark a significant stride forward in understanding malaria invasion mechanisms.

Professor Gerd Pluschke, Group Leader of Molecular Immunology at Swiss TPH and co-corresponding author of the study, said the role sugar plays in malaria infiltration process is a lot clearer.

“We are now demonstrating that P. falciparum CyRPA binds to a specific carbohydrate structure (glycan) present on the red blood cell surface. The CyRPA protein is highly adapted to bind to a glycan terminating with a sialic acid. The discovery of the key function of CyRPA in host cell invasion provides an explanation for the parasite inhibitory activity of CyRPA-specific antibodies.”

Professor Michael Jennings, Acting Director of the Institute for Glycomics and co-corresponding author, highlighted the evolutionary adaptation of the malaria parasite to humans.

“Humans differ from other primates because they can only produce one type of sialic acid, called Neu5Ac. This genetic difference between humans and closely related primates has long been proposed to contribute to the species-specific targeting of malaria parasites. In this study, we show that the human form of sialic acid, Neu5Ac, is strongly preferred by the human-specific malaria parasite P. falciparum, and may explain the adaptation of this parasite to humans.”

While vaccines targeting P. falciparum’s pre-erythrocytic stages have been registered for use, their efficacy remains moderate. Currently, there is no registered vaccine targeting the blood stage of malaria, but ongoing research worldwide and by many groups focuses intensively on this aspect.

“The discovery of the key function of CyRPA in host cell invasion strongly supports the concept to clinically test CyRPA as a blood stage vaccine target,” Professor Pluschke said.

The study’s findings offer promising avenues for novel antimalarial drugs according to Professor Jennings.

“The essential binding activity of CyRPA to a specific glycan also validates CyRPA as a drug target, and we demonstrate that small molecule inhibitors that interfere with this function can inhibit malaria replication in our study.”

This breakthrough not only sheds light on the intricate mechanisms of malaria invasion but also paves the way for innovative strategies in combating this pervasive global health challenge.

Griffith University continues to conduct world-leading research and development into potential malaria vaccines and therapies with Professor Michael Good AO and his Institute for Glycomics team conducting clinical trials for a novel ‘freeze dried’ vaccine while  Professor Katherine Andrews is leading research into potential malaria drug developments through her work at Griffith Institute for Drug Discovery (GRIDD) where she is Director.

10: Reduced Inequalities
UN Sustainable Development Goals 10: Reduced Inequalities