Plasmodium falciparum rosetting protects schizonts against artemisinin

Background: Artemisinin (ART) resistance in Plasmodium falciparum is thought to occur during the early stage of the parasite's erythrocytic cycle. Here, we identify a novel factor associated with the late stage parasite development that contributes to ART resistance. Methods: Rosetting rates o...

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Main Authors: Lee, Wenn-Chyau, Russell, Bruce, Lee, Bernett, Chu, Cindy S., Phyo, Aung Pyae, Sriprawat, Kanlaya, Lau, Yee-Ling, Nosten, François, Rénia, Laurent
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/154208
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spelling sg-ntu-dr.10356-1542082023-02-28T17:11:09Z Plasmodium falciparum rosetting protects schizonts against artemisinin Lee, Wenn-Chyau Russell, Bruce Lee, Bernett Chu, Cindy S. Phyo, Aung Pyae Sriprawat, Kanlaya Lau, Yee-Ling Nosten, François Rénia, Laurent Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences A*STAR Infectious Diseases Labs, A*STAR Singapore Immunology Network, A*STAR Science::Medicine Science::Biological sciences Artemisinin Resistance Plasmodium Falciparum Background: Artemisinin (ART) resistance in Plasmodium falciparum is thought to occur during the early stage of the parasite's erythrocytic cycle. Here, we identify a novel factor associated with the late stage parasite development that contributes to ART resistance. Methods: Rosetting rates of clinical isolates pre- and post- brief (one hour) exposure to artesunate (AS, an ART derivative) were evaluated. The effects of AS-mediated rosetting on the post-AS-exposed parasite's replication and survival, as well as the extent of protection by AS-mediated rosetting on different parasite stages were investigated. The rosetting ligands, mechanisms, and gene mutations involved were studied. Findings: Brief AS exposure stimulated rosetting, with AS-resistant isolates forming more rosettes in a more rapid manner. AS-mediated rosetting enabled infected erythrocytes (IRBC) to withstand AS exposure for several hours and protected the IRBC from phagocytosis. When their rosetting ability was blocked experimentally, the post-AS exposure survival advantage by the AS-resistant parasites was abrogated. Deletions in two genes coding for PfEMP1 exon 2 (PF3D7_0200300 and PF3D7_0223300) were found to be associated with AS-mediated rosetting, and these mutations were significantly selected through time in the parasite population under study, along with the K13 mutations, a molecular marker of ART-resistance. Interpretation: Rapid ART parasite clearance is driven by the direct oxidative damages on IRBC by ART and the phagocytic destruction of the damaged IRBC. Rosetting serves as a rapid ‘buying time’ strategy that allows more parasites to complete schizont maturation, reinvasion and subsequent development into the intrinsically less ART-susceptible ring stage. Agency for Science, Technology and Research (A*STAR) Published version WL, BL and LR were supported by core funding from A*STAR. WL was also funded by the Open Fund- Young Individual Research Grant (OF-YIRG NMRC/OFYIRG/0070/2018). LR was also funded by A*STAR grant (JCO-DP BMSI/15-800006-SIGN). BR was supported by a HRC eASIA grant (17/678). SMRU is part of the Mahidol-Oxford University Research Unit, supported by the Wellcome Trust of the Great Britain. 2022-05-24T08:26:38Z 2022-05-24T08:26:38Z 2021 Journal Article Lee, W., Russell, B., Lee, B., Chu, C. S., Phyo, A. P., Sriprawat, K., Lau, Y., Nosten, F. & Rénia, L. (2021). Plasmodium falciparum rosetting protects schizonts against artemisinin. EBioMedicine, 73, 103680-. https://dx.doi.org/10.1016/j.ebiom.2021.103680 2352-3964 https://hdl.handle.net/10356/154208 10.1016/j.ebiom.2021.103680 34749300 2-s2.0-85118578088 73 103680 en OF-YIRG NMRC/OFYIRG/0070/2018 JCO-DP BMSI/15-800006-SIGN EBioMedicine © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Science::Biological sciences
Artemisinin Resistance
Plasmodium Falciparum
spellingShingle Science::Medicine
Science::Biological sciences
Artemisinin Resistance
Plasmodium Falciparum
Lee, Wenn-Chyau
Russell, Bruce
Lee, Bernett
Chu, Cindy S.
Phyo, Aung Pyae
Sriprawat, Kanlaya
Lau, Yee-Ling
Nosten, François
Rénia, Laurent
Plasmodium falciparum rosetting protects schizonts against artemisinin
description Background: Artemisinin (ART) resistance in Plasmodium falciparum is thought to occur during the early stage of the parasite's erythrocytic cycle. Here, we identify a novel factor associated with the late stage parasite development that contributes to ART resistance. Methods: Rosetting rates of clinical isolates pre- and post- brief (one hour) exposure to artesunate (AS, an ART derivative) were evaluated. The effects of AS-mediated rosetting on the post-AS-exposed parasite's replication and survival, as well as the extent of protection by AS-mediated rosetting on different parasite stages were investigated. The rosetting ligands, mechanisms, and gene mutations involved were studied. Findings: Brief AS exposure stimulated rosetting, with AS-resistant isolates forming more rosettes in a more rapid manner. AS-mediated rosetting enabled infected erythrocytes (IRBC) to withstand AS exposure for several hours and protected the IRBC from phagocytosis. When their rosetting ability was blocked experimentally, the post-AS exposure survival advantage by the AS-resistant parasites was abrogated. Deletions in two genes coding for PfEMP1 exon 2 (PF3D7_0200300 and PF3D7_0223300) were found to be associated with AS-mediated rosetting, and these mutations were significantly selected through time in the parasite population under study, along with the K13 mutations, a molecular marker of ART-resistance. Interpretation: Rapid ART parasite clearance is driven by the direct oxidative damages on IRBC by ART and the phagocytic destruction of the damaged IRBC. Rosetting serves as a rapid ‘buying time’ strategy that allows more parasites to complete schizont maturation, reinvasion and subsequent development into the intrinsically less ART-susceptible ring stage.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Lee, Wenn-Chyau
Russell, Bruce
Lee, Bernett
Chu, Cindy S.
Phyo, Aung Pyae
Sriprawat, Kanlaya
Lau, Yee-Ling
Nosten, François
Rénia, Laurent
format Article
author Lee, Wenn-Chyau
Russell, Bruce
Lee, Bernett
Chu, Cindy S.
Phyo, Aung Pyae
Sriprawat, Kanlaya
Lau, Yee-Ling
Nosten, François
Rénia, Laurent
author_sort Lee, Wenn-Chyau
title Plasmodium falciparum rosetting protects schizonts against artemisinin
title_short Plasmodium falciparum rosetting protects schizonts against artemisinin
title_full Plasmodium falciparum rosetting protects schizonts against artemisinin
title_fullStr Plasmodium falciparum rosetting protects schizonts against artemisinin
title_full_unstemmed Plasmodium falciparum rosetting protects schizonts against artemisinin
title_sort plasmodium falciparum rosetting protects schizonts against artemisinin
publishDate 2022
url https://hdl.handle.net/10356/154208
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