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Professors Matthew Higgins and Michael Dustin from the University of Oxford, Prof Gavin Wright from the University of York, and Professors Shiroh Iwanaga and Hisashi Arase from Osaka University have secured a Wellcome Collaborative Award for their study “How do RIFINs and STEVORs modulate human immunity during malaria?”

Mosquito on skin © SHUTTERSTOCK

The £2M Wellcome Collaborative Award will fund a 5-year project to explore how the malaria parasite can deceive the human immune system.

Malaria is a serious disease caused by a parasite which is spread to humans through the bite of an infected mosquito. The tiny parasites that cause malaria hide within human red blood cells where they replicate and mature. However, the human immune system mounts a defence and responds by activating its immune cells to seek out and destroy infected red blood cells before the parasite matures, leading to parasite death, while sparing uninfected cells. To allow them to do this, our cells present molecules, such as major histocompatibility complex (MHC) on their surfaces, signalling to our immune cells that they are part of our bodies.

The malaria parasite has evolved a large family of proteins, called RIFINs and STEVORs, that are presented on infected blood cell surfaces. Previous work from partners in Osaka recently found that some of the RIFINs shield the infected red blood cells by shutting down signals in the immune cells, thereby protecting the parasite from detection.

The Oxford and Osaka teams published in 2020 in Nature that this RIFIN can mimic human molecules, such as MHC, that protect healthy cells from immune attack. The aim of the new research is to discover if other RIFINs do the same to better understand if this discovery may be harnessed to better treat malaria.

Professor Michael Dustin, Director of Research at the Kennedy Institute, Oxford said: "I am delighted to be part of the team receiving this prestigious collaborative award. It's an exciting project to understand if this entire family of proteins work in this way or in different ways. The limited examples we have suggest that RIFINs act like checkpoints in cancer- using mechanisms designed to prevent autoimmunity to protect the parasitised red blood cells. I expect there will be more surprises and hopefully some vulnerabilities of the parasite that can be developed into treatments."

The collaborative effort brings together the latest tools and expertise in transgenic parasite biology, structural biology, biophysics of cell interfaces and high-throughput technology.

Matthew Higgins, Professor of Molecular Parasitology at the Department of Biochemistry at Oxford said: "By teaming up we are able to bring together experts in a wide range of different techniques, giving us the chance to answer fundamental questions about how the malaria parasite tricks our immune system. We think that this will also give us clues about how immunity works."

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