A remarkable evolutionary battle between humans and malaria

Our immune systems use powerful cells, the natural killer cells, to patrol our bodies, looking for pathogens. When they bump into another cell, they need to decide whether it is one of our own cells, and to let it live, or whether it is a pathogen and should be destroyed. To help them to make this decision, they use immune receptors. Our own cells bind to the inhibitory immune receptors on the killer cells, reducing their function. In contrast, the activating immune receptors on the killer cells bind to pathogens, causing the killer cell to deploy a deadly set of toxins.

Previous work has shown that red blood cells infected with the malaria parasite, Plasmodium falciparum, place a set of proteins, the RIFINs, on their surfaces. There are many hundreds of RIFINs and some of them bind to inhibitory immune receptors, such as LILRB1, and suppress natural killer cell function.

In this latest study, our collaborators from the University of Osaka, Akihito Sakoguchi, Shiroh Iwanaga and Hisashi Arase found a new set of RIFINs which bind to the inhibitory immune receptor, KIR2DL1. Sam Chamberlain was able show, using structural studies, how these RIFINs bind to KIRs. Working with Alex Mørch and Mike Dustin, we were also able to show that the RIFINs can signal through KIR2DL1, suppressing KIR function.

The surprise came when we found that these RIFINs also bind to an activating KIR receptor, KIR2DS1. The KIRs are known as paired receptors, with these pairs containing one inhibitory and one activating receptor. These share very similar extracellular ligand binding domains but result in the opposite type of signalling event when triggered. The same RIFINs that bind to inhibitory receptor KIR2DL1 also bind to activating receptor KIR2DS1. If the natural killer cell has KIR2DS1 on its surface, then we find that binding to the RIFIN triggers it to kill parasite-infected blood cells.

What does this mean? We think that it is likely that the activating immune receptor KIR2DS1 evolved to destroy malaria parasites by recognising those very same RIFINs which the parasite had evolved to suppress natural killer cell function. We are therefore seeing a snapshot of the evolutionary battle between humans and this ancient foe. With many hundreds of RIFINs still with unknown function, we are excited to see what else they teach us about both the parasite and our immune systems.

Sakoguchi, A.†, Chamberlain, S.G.†, Mørch, A.M., Harrison, T.E., Dustin, M.L., Arase, H.*,Higgins, M.K.*, Iwanaga S.* (2024) RIFINs displayed on malaria-infected erythrocytes bind both KIR2DL1 and KIR2DS1. BioRXIV doi.org/10.1101/2024.04.30.591854 († equal contribution, * equal corresponding)