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 of...
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th-mahidol.759772022-08-04T15:04:33Z Plasmodium falciparum rosetting protects schizonts against artemisinin Wenn Chyau Lee Bruce Russell Bernett Lee Cindy S. Chu Aung Pyae Phyo Kanlaya Sriprawat Yee Ling Lau François Nosten Laurent Rénia A-Star, Infectious Disease Lab Faculty of Tropical Medicine, Mahidol University A-Star, Singapore Immunology Network School of Biological Sciences Universiti Malaya University of Otago Nuffield Department of Medicine Nanyang Technological University Biochemistry, Genetics and Molecular Biology 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. Funding: A*STAR, NMRC-OF-YIRG, HRC e-ASIA, Wellcome. 2022-08-04T08:04:33Z 2022-08-04T08:04:33Z 2021-11-01 Article eBioMedicine. Vol.73, (2021) 10.1016/j.ebiom.2021.103680 23523964 2-s2.0-85118578088 https://repository.li.mahidol.ac.th/handle/123456789/75977 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85118578088&origin=inward |
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Biochemistry, Genetics and Molecular Biology Wenn Chyau Lee Bruce Russell Bernett Lee Cindy S. Chu Aung Pyae Phyo Kanlaya Sriprawat Yee Ling Lau François Nosten Laurent Rénia Plasmodium falciparum rosetting protects schizonts against artemisinin |
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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. Funding: A*STAR, NMRC-OF-YIRG, HRC e-ASIA, Wellcome. |
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A-Star, Infectious Disease Lab |
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A-Star, Infectious Disease Lab Wenn Chyau Lee Bruce Russell Bernett Lee Cindy S. Chu Aung Pyae Phyo Kanlaya Sriprawat Yee Ling Lau François Nosten Laurent Rénia |
format |
Article |
author |
Wenn Chyau Lee Bruce Russell Bernett Lee Cindy S. Chu Aung Pyae Phyo Kanlaya Sriprawat Yee Ling Lau François Nosten Laurent Rénia |
author_sort |
Wenn Chyau Lee |
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://repository.li.mahidol.ac.th/handle/123456789/75977 |
_version_ |
1763487756870221824 |