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Title: Plasmodium falciparum rosetting protects schizonts against artemisinin
Authors: Lee, Wenn-Chyau
Russell, Bruce
Lee, Bernett
Chu, Cindy S.
Phyo, Aung Pyae
Sriprawat, Kanlaya
Lau, Yee-Ling
Nosten, François
Rénia, Laurent
Keywords: Science::Medicine
Science::Biological sciences
Issue Date: 2021
Source: 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-.
Project: OF-YIRG NMRC/OFYIRG/0070/2018
JCO-DP BMSI/15-800006-SIGN
Journal: EBioMedicine
Abstract: 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.
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2021.103680
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Biological Sciences 
Organisations: A*STAR Infectious Diseases Labs, A*STAR
Singapore Immunology Network, A*STAR
Rights: © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

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