How some human genes protect against malaria

Silvia Kariuki is a Kenyan Geneticist and research scientist at the KEMRI-Wellcome Trust Research Programme (KWTRP). She is also a DELTAS Africa Postdoctoral Fellow at IDeAL. IDeAL (Initiative to Develop African Research Leaders) is one of the eleven Developing Excellence, Leadership, and Training in Science in Africa (DELTAS Africa) programmes. DELTAS Africa funds Africa-based scientists to amplify the development of world-class research and scientific leadership on the continent while strengthening African institutions. DELTAS Africa is implemented through the AESA Platform. AESA (The Alliance for Accelerating Excellence in Science in Africa) is a funding, agenda-setting, programme management initiative of the African Academy of Sciences (AAS), the African Union Development Agency (AUDA-NEPAD), founding and funding global partners, and through a resolution of the summit of African Union Heads of Governments. DELTAS Africa is supported by Wellcome and the United Kingdom Foreign, Commonwealth and Development Office (FCDO formerly DFID).

Summary

The Dantu blood group, a novel red blood cell gene variant found at highest frequency in Kilifi in the Kenyan coastal region, confers upto 74% protection from severe malaria infection. This is a protective effect that is similar in magnitude to the sickle cell trait, and considerably greater than the best malaria vaccine candidate. The goal of this study was to investigate the mechanism through which the Dantu blood group variant confers its protective effect. We found a strong correlation between red blood cell membrane tension and parasite invasion ability, where increased membrane tension leads to resistance to parasite invasion. We found that Dantu red blood cells had above average tension, meaning that a greater proportion resisted invasion.

Burden of Malaria

Malaria has been the biggest cause of childhood mortality globally over the last five thousand years; mortality remains high in many countries, with over 90% of the estimated 409,000 deaths from malaria in 2019 occurring in Africa. The growing resistance of the Plasmodium falciparum parasite and its mosquito transmitters? against current treatments for malaria means that finding new approaches for combating the disease is of growing importance. Malaria has had a strong impact on the human genome, leading to selection of several genetic variants, such as sickle cell trait, alpha thalassaemia and the Dantu blood group to high frequencies in malaria-endemic populations. Understanding how these genetic variants confer their protective effects could inform novel preventive and therapeutic approaches to malaria prevention and treatment.

Investigating the protective effect of the Dantu blood group variant

In collaboration with colleagues at the Wellcome Sanger Institute and the University of Cambridge Cavendish Laboratory, we carried out a series of experiments using flow cytometry, said another way simply…, and live video microscopy to investigate how the Dantu variant confers its strongly protective effect. We observed a significantly reduced ability of the Plasmodium falciparum parasite to invade Dantu red blood cells. This inhibition was linked to a change in the biophysical properties of these cells, where there was a strong link between parasite invasion efficiency and RBC membrane tension. We identified a membrane tension threshold above which parasite invasion rarely occurred. Dantu RBCs had significantly above average membrane tension that resulted in resistance to parasite invasion.

These findings provide critical insights into the interactions between the human host and the malaria parasite, adding a new dimension to our molecular understanding of red blood cell invasion by the P. falciparum malaria parasite. This study highlights how a host genetic variant found at the highest frequency in a Kenyan population confers a strongly protective effect against malaria, which we hope will inform the development of future treatment for malaria.