4.7 Article

Plasmodium falciparum rosetting protects schizonts against artemisinin

期刊

EBIOMEDICINE
卷 73, 期 -, 页码 -

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ELSEVIER
DOI: 10.1016/j.ebiom.2021.103680

关键词

Artemisinin resistance; Plasmodium falciparum rosetting; PfEMP1

资金

  1. A*STAR [JCO-DP BMSI/15-800006-SIGN]
  2. Open Fund-Young Individual Research Grant [OF-YIRG NMRC/OFYIRG/0070/2018]
  3. HRC eASIA grant [17/678]
  4. Wellcome Trust of the Great Britain

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Brief exposure to artesunate (AS) stimulates rosetting, with AS-resistant isolates forming more rosettes rapidly for protection. Deletions in genes associated with AS-mediated rosetting are significantly selected in the parasite population, along with the K13 mutations as a marker of ART resistance.
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.

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