ORIGINAL RESEARCH article
Front. Cell. Infect. Microbiol.
Sec. Parasite and Host
Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1553123
Chloroquine induces eryptosis in P. falciparum-infected red blood cells and the release of extracellular vesicles with a unique protein profile
Provisionally accepted
Kevin SW Tan1*
Claudia Carrera Bravo1
Tianchi Zhou2
Trang Chu1
Jing Wen Hang1Harshvardhan Modh1
Chenyuan Huang1Sitong Zhang1
Haining Hao1
María José Cabada-García1
Benoit Malleret1
Matthias G. Wacker1
Jiong-Wei Wang1
Laurent Rénia3- 1National University of Singapore, Singapore, Singapore
- 2University of Edinburgh, Edinburgh, Scotland, United Kingdom
- 3A*STAR Infectious Disease Labs, Singapore, Singapore
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Malaria is a vector-borne parasitic disease that affects millions worldwide. In order to reach the objective set by the World Health Organization to decrease the cases by 2030, antimalarial drugs with novel modes of action are required. Previously, a novel mechanism of action of chloroquine (CQ) was reported involving features of programmed cell death in the parasite, mainly characterized by calcium efflux from digestive vacuole (DV) permeabilization. Increased intracellular calcium induces suicidal death of erythrocytes also known as eryptosis. This study aimed to identify the hallmarks of eryptosis due to calcium redistribution and the downstream cellular effects during CQ treatment in iRBCs. Plasmodium falciparum 3D7 at mid-late trophozoites were used for the antimalarial drug treatment. Our results revealed increased phosphatidylserine (PS) exposure, cell shrinkage, and membrane blebbing, delineating an eryptotic phenotype in the host RBC. Interestingly, the outward budding and blebbing of the iRBCs plasma membrane forms extracellular vesicles (EVs) which are complex structures with unique functional properties. Proteomic characterization of EVs from CQ-treated iRBCs displayed highly enriched proteasome and ribosome protein clusters. We demonstrated that this unique EV cargo did not influence parasite growth rate but might activate IFN signaling pathways mediated by IL-6 in THP-1-derived macrophages. Our findings shed new insights into a novel drug-induced cell death mechanism that targets the parasite and specific components of the infected host RBC.
Keywords: eryptosis, Plasmodium falciparum, Chloroquine, extracellular vesicles, Proteomics, Hostparasite interaction
Received: 30 Dec 2024; Accepted: 30 Apr 2025.
Copyright: © 2025 Tan, Bravo, Zhou, Chu, Hang, Modh, Huang, Zhang, Hao, Cabada-García, Malleret, Wacker, Wang and Rénia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Kevin SW Tan, National University of Singapore, Singapore, Singapore
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