Scientists at the Swiss Tropical and Public Health Institute and Australia's Institute for Glycomics have cracked a crucial puzzle about how malaria parasites breach the bodies' red blood cells—a discovery that could reshape the search for vaccines and drugs against one of humanity's deadliest infectious diseases.
For decades, researchers knew that the malaria parasite Plasmodium falciparum relies on a protein called CyRPA (cysteine-rich protective antigen) to invade red blood cells, but they didn't understand exactly how this protein accomplishes its task. A multidisciplinary team from six institutions has now revealed the missing piece: the parasite targets a sugar called sialic acid on the surface of red blood cells, and CyRPA is exquisitely adapted to bind to one specific form of this sugar called Neu5Ac.
The finding matters because malaria remains a staggering global burden. In 2022 alone, there were 249 million cases and 608,000 deaths worldwide, with Plasmodium falciparum responsible for the vast majority of severe cases and deaths. All the clinical symptoms of malaria—fever, organ damage, death—stem from parasites multiplying inside red blood cells. Understanding how they get inside is therefore a race against the clock.
The research, published in the journal Cell Reports, reveals something elegant about the parasite's evolution: humans differ genetically from closely related primates in that they can only produce one type of sialic acid, Neu5Ac. P. falciparum has become finely tuned to prefer exactly this form. "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," said Michael Jennings, acting director of the Institute for Glycomics. This genetic mismatch between human and other primate sialic acids has long been suspected to explain why malaria parasites home in so precisely on humans—and now there is hard evidence to support it.
The implications for treatment are substantial. Current malaria vaccines targeting the parasite's early stages show only moderate effectiveness. Blood-stage vaccines, which would block parasites from invading or surviving in red blood cells, remain in research phases with no licensed version yet available. The discovery of CyRPA's exact function "strongly supports the concept to clinically test CyRPA as a blood stage vaccine target," according to Gerd Pluschke, group leader of molecular immunology at Swiss TPH. This opens a concrete path forward for vaccine developers.
Drug development may move even faster. As parasites worldwide increasingly resist existing antimalarial drugs—a crisis that threatens to erase decades of progress—researchers need new targets urgently. Jennings' team demonstrated that small molecule inhibitors can block CyRPA's binding activity and prevent malaria replication in laboratory studies. "The essential binding activity of CyRPA to a specific glycan also validates CyRPA as drug target," Jennings said, suggesting that pharmaceutical companies now have a well-defined molecular bull's-eye to aim at.
What began as a puzzle about protein function has become a potential turning point in the fight against malaria. By revealing how the parasite recognizes and invades its human host, scientists have handed forward generations of researchers and drug developers a blueprint for attack.