A remarkable evolutionary battle between humans and malaria

Sam Chamberlain

In a ground-breaking study published in Nature, University of Oxford researchers Sam Chamberlain (left) and Matt Higgins, in collaboration with scientists from Osaka University and the Kennedy Institute, have unveiled new insights into the ongoing evolutionary battle between humans and the malaria parasite. The international team has discovered how the malaria parasite evades the immune system—and how the human body fights back.

‘Natural killer’ cells, a key component of the immune system, patrol the body to identify and destroy infected or abnormal cells. These cells rely on a balance of activating and inhibitory receptors to determine whether a cell is friend or foe. When these natural killer cells encounter a pathogen, activating receptors trigger a lethal response, while inhibitory receptors prevent attacks on the body’s own cells.

The malaria parasite Plasmodium falciparum has evolved a cunning strategy to escape detection. It disguises infected red blood cells with a diverse family of proteins known as RIFINs. Some RIFINs bind to inhibitory receptors like LILRB1 on natural killer cells, effectively disarming them.

In the latest study, researchers from Osaka University—Akihito Sakoguchi, Shiroh Iwanaga, and Hisashi Arase—identified a new subset of RIFINs that bind to another inhibitory receptor, KIR2DL1. Structural studies led by Sam Chamberlain then revealed how these RIFINs interact with KIRs, and further studies with Alex Mørch, Marcus Widdess and Mike Dustin from the Kennedy Institute demonstrated that this interaction suppresses natural killer cell activity.

However, the team made a surprising discovery: the same RIFINs that bind to the inhibitory receptor KIR2DL1 also bind to its activating counterpart, KIR2DS1. These paired receptors share similar structures but trigger opposite responses. When natural killer cells express KIR2DS1, binding to the RIFINs activates the cells, prompting them to kill the infected red blood cells.

“This suggests that KIR2DS1 may have evolved specifically to counteract the malaria parasite’s evasion tactics,” said Sam Chamberlain.

With many hundreds of RIFINs still with unknown function, the researchers believe this discovery is just the beginning. “Each new RIFIN we study could reveal more about how our immune system has adapted to fight this ancient and deadly foe,” Matt Higgins added.

The full study, titled “RIFINs displayed on malaria-infected erythrocytes bind both KIR2DL1 and KIR2DS1”, is available in Nature.

Sakoguchi, A.†, Chamberlain, S.G.†, Mørch, A.M., Widdess, M., Harrison, T.E., Dustin, M.L., Arase, H.*, Higgins, M.K.*, Iwanaga S.* (2025) RIFINs displayed on malaria-infected erythrocytes bind both KIR2DL1 and KIR2DS1. Nature († equal contribution, * equal corresponding)