Plasmodium falciparum rosetting protects schizonts against artemisinin

Lee, Wenn-Chyau and Russell, Bruce and Lee, Bernett and Chu, Cindy S. and Phyo, Aung Pyae and Sriprawat, Kanlaya and Lau, Yee Ling and Nosten, Francois and Renia, Laurent (2021) Plasmodium falciparum rosetting protects schizonts against artemisinin. Ebiomedicine, 73. ISSN 2352-3964, DOI

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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. (C) 2021 The Author(s). Published by Elsevier B.V.

Item Type: Article
Funders: Agency for Science Technology & Research (ASTAR) (JCO-DP BMSI/15-800006-SIGN), Open Fund-Young Individual Research Grant (OF-YIRG NMRC/OFYIRG/0070/2018), HRC eASIA grant (17/678), Wellcome Trust
Uncontrolled Keywords: Artemisinin resistance; Plasmodium falciparum rosetting; PfEMP1
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
Divisions: Faculty of Medicine > Parasitology Deparment
Depositing User: Ms Zaharah Ramly
Date Deposited: 08 Sep 2022 01:08
Last Modified: 08 Sep 2022 01:08

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