Plasmodium falciparum rosetting protects schizonts against artemisinin

• Published in: EBioMedicine Vol. 73; p. 103680
• Main Authors: Lee, Wenn-Chyau, Russell, Bruce, Lee, Bernett, Chu, Cindy S, Phyo, Aung Pyae, Sriprawat, Kanlaya, Lau, Yee-Ling, Nosten, François, Rénia, Laurent
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2021; Elsevier
• Subjects: Antimalarials - pharmacology; Antimalarials - therapeutic use; Artemisinin resistance; Artemisinins - pharmacology; Artemisinins - therapeutic use; Cell Line; Drug Resistance; Erythrocytes - parasitology; Erythrocytes - pathology; Humans; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Malaria, Falciparum - pathology; PfEMP1; Phagocytosis - immunology; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - physiology; Research paper; Rosette Formation; rosetting; Artemisinin resistance; Plasmodium falciparum; rosetting; PfEMP1
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2021.103680

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. 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. 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. 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. A*STAR, NMRC-OF-YIRG, HRC e-ASIA, Wellcome.