Researchers from The University of Osaka find that a protein expressed on malaria-infected red blood cells both hides it from the immune system and activates cells to destroy it, making it a promising target for vaccine development.

Osaka, Japan – Malaria is a life-threatening disease affecting people globally. It is spread by mosquitoes carrying Plasmodium parasites that infect and hide in red blood cells, making them difficult for the immune system to detect. Previous studies have shown that proteins expressed on the surface of malaria-infected red blood cells, known as repetitive interspersed family (RIFIN) proteins, can bind to immune cell receptors to protect the parasite. However, some interactions with natural killer (NK) cells and their receptors remained unknown.

In a recent study published in Nature, researchers from The University of Osaka have identified RIFIN-binding KIRs that both suppress and activate NK activity, highlighting the dual function of these proteins in enabling parasite survival and host protection.

NK cells identify and eliminate abnormal or infected cells, which they do by recognizing molecules on the cell surface. These signals bind the receptors on NK cells, causing them to either suppress their activity or to destroy target cells. Some receptors, such as killer immunoglobulin-like receptors (KIRs), are found in pairs and have nearly identical target-binding domains, meaning that parasites and diseases could be ‘sneaking past’ the immune system and allowing malaria to thrive.

“As inhibitory KIRs on NK cells are structurally similar to other inhibitory immune cell receptors that bind RIFINs, we wondered whether these KIR proteins would also interact with RIFINs on the surface of malaria-infected cells,” says corresponding author, Shiroh Iwanaga. “If this were the case, it would allow us to identify a new method used by malaria to evade the immune system.”

To do this, the researchers first screened cells infected by certain strains of Plasmodium falciparum and found an interaction between KIR2DL1 – one type of an inhibitory KIR – and a RIFIN expressed in infected cells. Further testing and structural modeling showed that multiple RIFINs from related strains were able to interact with KIR2DL1, initiating signaling to inhibit NK cell activity.

“We found that RIFINs capable of binding this receptor were very common across different malaria strains from Southeast Asia and Africa, indicating that the ability to inhibit NK activity happens across the globe,” explains Shiroh Iwanaga.

In a surprising twist and a global first, these RIFINs were also found to bind the activating KIR2DS1 receptor, which triggered NK cell activation to kill infected cells.

“Our findings suggest that RIFINs play two roles, both allowing the parasite to hide from the immune system as well as allowing the immune system to detect it,” says Iwanaga. “This dual role makes these KIR-binding RIFINs extremely promising targets for malaria treatment and prevention.”

Although there are several hundred million species of RIFINs, others with functions similar to those identified in this study are common among strains of malaria. This makes the RIFINs excellent targets for the development of new malaria treatments and vaccines to combat this deadly disease.
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The article, “RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1,” was published in Nature at DOI: https://doi.org/10.1038/s41586-025-09091-y.