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Red blood cell tension controls Plasmodium falciparum invasion and protects against severe malaria in the Dantu blood group

View ORCID ProfileSilvia N. Kariuki, Alejandro Marin-Menendez, Viola Introini, Benjamin J. Ravenhill, Yen-Chun Lin, Alex Macharia, Johnstone Makale, Metrine Tendwa, Wilfred Nyamu, Jurij Kotar, Manuela Carrasquilla, J. Alexandra Rowe, Kirk Rockett, Dominic Kwiatkowski, Michael P. Weekes, Pietro Cicuta, Thomas N. Williams, View ORCID ProfileJulian C. Rayner
doi: https://doi.org/10.1101/475442
Silvia N. Kariuki
1KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
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  • ORCID record for Silvia N. Kariuki
Alejandro Marin-Menendez
2Wellcome Sanger Institute, Cambridge, UK
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Viola Introini
3Cavendish Laboratory, University of Cambridge, Cambridge, UK
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Benjamin J. Ravenhill
4Cambridge Institute for Medical Research, Cambridge, UK
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Yen-Chun Lin
3Cavendish Laboratory, University of Cambridge, Cambridge, UK
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Alex Macharia
1KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
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Johnstone Makale
1KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
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Metrine Tendwa
1KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
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Wilfred Nyamu
1KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
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Jurij Kotar
3Cavendish Laboratory, University of Cambridge, Cambridge, UK
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Manuela Carrasquilla
2Wellcome Sanger Institute, Cambridge, UK
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J. Alexandra Rowe
5University of Edinburgh, Edinburgh, UK
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Kirk Rockett
6Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
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Dominic Kwiatkowski
2Wellcome Sanger Institute, Cambridge, UK
6Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
7Big Data Institute, University of Oxford, Oxford, UK
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Michael P. Weekes
4Cambridge Institute for Medical Research, Cambridge, UK
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Pietro Cicuta
3Cavendish Laboratory, University of Cambridge, Cambridge, UK
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  • For correspondence: pc245@cam.ac.uk twilliams@kemri-wellcome.org julian.rayner@sanger.ac.uk
Thomas N. Williams
1KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
8Imperial College London, London, UK
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  • For correspondence: pc245@cam.ac.uk twilliams@kemri-wellcome.org julian.rayner@sanger.ac.uk
Julian C. Rayner
2Wellcome Sanger Institute, Cambridge, UK
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  • ORCID record for Julian C. Rayner
  • For correspondence: pc245@cam.ac.uk twilliams@kemri-wellcome.org julian.rayner@sanger.ac.uk
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Abstract

Malaria has had a major effect on the human genome, with many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemic regions1, 2. Recently, we showed that a novel blood group variant, Dantu, provides 74% protection against all forms of severe malaria in homozygous individuals3-5. This is a similar degree of protection to sickle cell trait and considerably greater than the most advanced malaria vaccine, but until now the mechanism of protection has been unknown. In the current study, we demonstrate a significant impact of Dantu on the ability of Plasmodium falciparum merozoites to invade RBCs. The Dantu variant was associated with extensive changes to the RBC surface protein repertoire, but unexpectedly the malaria protective effect did not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we found a strong link between RBC tension and parasite invasion and, even in non-Dantu RBCs, identified a tension threshold above which RBC invasion did not occur. Dantu RBCs had higher average tension, meaning that a higher proportion of Dantu RBCs could not be invaded. These findings not only provide an explanation for the protective effect of Dantu against severe malaria, but also provide fresh insights into the essential process of P. falciparum parasite invasion, and how invasion efficiency varies across the heterogenous populations of RBCs that are present both within and between individuals.

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Posted November 22, 2018.
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Red blood cell tension controls Plasmodium falciparum invasion and protects against severe malaria in the Dantu blood group
Silvia N. Kariuki, Alejandro Marin-Menendez, Viola Introini, Benjamin J. Ravenhill, Yen-Chun Lin, Alex Macharia, Johnstone Makale, Metrine Tendwa, Wilfred Nyamu, Jurij Kotar, Manuela Carrasquilla, J. Alexandra Rowe, Kirk Rockett, Dominic Kwiatkowski, Michael P. Weekes, Pietro Cicuta, Thomas N. Williams, Julian C. Rayner
bioRxiv 475442; doi: https://doi.org/10.1101/475442
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Red blood cell tension controls Plasmodium falciparum invasion and protects against severe malaria in the Dantu blood group
Silvia N. Kariuki, Alejandro Marin-Menendez, Viola Introini, Benjamin J. Ravenhill, Yen-Chun Lin, Alex Macharia, Johnstone Makale, Metrine Tendwa, Wilfred Nyamu, Jurij Kotar, Manuela Carrasquilla, J. Alexandra Rowe, Kirk Rockett, Dominic Kwiatkowski, Michael P. Weekes, Pietro Cicuta, Thomas N. Williams, Julian C. Rayner
bioRxiv 475442; doi: https://doi.org/10.1101/475442

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