Dataset Information

Resistance to malaria through structural variation of red blood cell invasion receptors.

ABSTRACT: The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.

SUBMITTER: Leffler EM

PROVIDER: S-EPMC5575826 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Resistance to malaria through structural variation of red blood cell invasion receptors.

Leffler Ellen M EM Band Gavin G Busby George B J GBJ Kivinen Katja K Le Quang Si QS Clarke Geraldine M GM Bojang Kalifa A KA Conway David J DJ Jallow Muminatou M Sisay-Joof Fatoumatta F Bougouma Edith C EC Mangano Valentina D VD Modiano David D Sirima Sodiomon B SB Achidi Eric E Apinjoh Tobias O TO Marsh Kevin K Ndila Carolyne M CM Peshu Norbert N Williams Thomas N TN Drakeley Chris C Manjurano Alphaxard A Reyburn Hugh H Riley Eleanor E Kachala David D Molyneux Malcolm M Nyirongo Vysaul V Taylor Terrie T Thornton Nicole N Tilley Louise L Grimsley Shane S Drury Eleanor E Stalker Jim J Cornelius Victoria V Hubbart Christina C Jeffreys Anna E AE Rowlands Kate K Rockett Kirk A KA Spencer Chris C A CCA Kwiatkowski Dominic P DP

Science (New York, N.Y.) 20170518 6343

The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB We find that a nearby association with severe malaria is explained by a complex structural rearrangement invo ...[more]

PMID: 28522690

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Project description:A critical step in how malaria parasites invade red blood cells (RBCs) is the wrapping of the membrane around the egg-shaped merozoites. Recent experiments have revealed that RBCs can be protected from malaria invasion by high membrane tension. While cellular and biochemical aspects of parasite actomyosin motor forces during the malaria invasion have been well studied, the important role of the biophysical forces induced by the RBC membrane-cytoskeleton composite has not yet been fully understood. In this study, we use a theoretical model for lipid bilayer mechanics, cytoskeleton deformation, and membrane-merozoite interactions to systematically investigate the influence of effective RBC membrane tension, which includes contributions from the lipid bilayer tension, spontaneous tension, interfacial tension, and the resistance of cytoskeleton against shear deformation on the progression of membrane wrapping during the process of malaria invasion. Our model reveals that this effective membrane tension creates a wrapping energy barrier for a complete merozoite entry. We calculate the tension threshold required to impede the malaria invasion. We find that the tension threshold is a nonmonotonic function of spontaneous tension and undergoes a sharp transition from large to small values as the magnitude of interfacial tension increases. We also predict that the physical properties of the RBC cytoskeleton layer-particularly the resting length of the cytoskeleton-play key roles in specifying the degree of the membrane wrapping. We also found that the shear energy of cytoskeleton deformation diverges at the full wrapping state, suggesting the local disassembly of the cytoskeleton is required to complete the merozoite entry. Additionally, using our theoretical framework, we predict the landscape of myosin-mediated forces and the physical properties of the RBC membrane in regulating successful malaria invasion. Our findings on the crucial role of RBC membrane tension in inhibiting malaria invasion can have implications for developing novel antimalarial therapeutic or vaccine-based strategies.

Dataset Information

Resistance to malaria through structural variation of red blood cell invasion receptors.

Publications

Resistance to malaria through structural variation of red blood cell invasion receptors.

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