Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum

Chen, Jiayun1,2,3,4; Gao, Peng1,2; Xiao, Wei5; Cheng, Guangqing1,2; Krishna, Sanjeev6,7,8; Wang, Jianyou1,2; Wong, Yin Kwan3,4; Wang, Chen1,2; Gu, Liwei1,2; Yang, Dong Hua9; Wang, Jigang1,2,3,4

2023-09-01

10.1016/j.drup.2023.100978

DRUG RESISTANCE UPDATES   Impact Factor & Quartile

1368-7646

1532-2084

Aims: We investigated the stage-specific mechanisms of partial resistance to artemisinin (ART, an antimalarial drug) in Plasmodium falciparum (P. falciparum) carrying the Kelch13 C580Y mutation. Methods: Using fluorescence labeling and activity-based protein profiling, we systematically profile the ART activation levels in P. falciparum during the entire intra-erythrocytic developmental cycle (IDC), and determined the ART-targets profile of the ART-sensitive and -resistant strains at different stages. We retrieved and integrated datasets of single-cell transcriptomics and label-free proteomics across three IDC stages of wild-type P. falciparum. We also employed lipidomics to validate lipid metabolic reprogramming in the resistant strain.Results: The activation and expression patterns of genes and proteins of ART-targets in both ART-sensitive and resistant strains varied at different stages and periods of P. falciparum development, with the late trophozoite stage harboring the largest number of ART targets. We identified and validated 36 overlapping targets, such as GAPDH, EGF-1a, and SpdSyn, during the IDC stages in both strains. We revealed the ART-insensitivity of fatty acid-associated activities in the partially resistant strain at both the early ring and early trophozoite stages.Conclusions: Our multi-omics strategies provide novel insights into the mechanisms of ART partial resistance in Kelch13 mutant P. falciparum, demonstrating the stage-specific interaction between ART and malaria parasites.

Artemisinin Plasmodium falciparum Artemisinin target Activity-based protein profiling Artemisinin resistance

SCI

English

Corresponding

National Key Research and Development Program of China[2020YFA0908000] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-C-202002] ; National Natural Science Foundation of China["82141001","82274182","82074098","82173914"] ; CACMS Innovation Fund["CI2021A05101","CI2021A05104"] ; Introduce Innovative Team Projects of Jinan[202228029] ; Shenzhen Key Laboratory of Prevention and Treatment of Severe Infections[ZDSYS20200811142804014] ; Fundamental Research Funds for the Central Public Welfare Research Institutes["ZZ14-YQ-050","ZZ14-YQ-051","ZZ14-YQ-052","ZZ14-FL-002","ZZ14-ND-010","ZZ15-ND-10"]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:001037419900001

CHURCHILL LIVINGSTONE

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.China Acad Chinese Med Sci, Artemisinin Res Ctr, Beijing 100700, Peoples R China
2.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Dept Crit Med, Shenzhen 518020, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Clin Res Ctr Geriatr, Shenzhen 518020, Guangdong, Peoples R China
5.Guangdong Pharmaceut Univ, Key Lab Glucolipid Metab Disorder, Minist Educ, Guangzhou 510006, Guangdong, Peoples R China
6.St Georges Univ London, Inst Infect & Immun, Clin Acad Grp, London, England
7.St Georges Univ Hosp NHS Fdn Trust, London, England
8.Univ Klinikum Tubingen, Inst Tropenmed, Tubingen, Germany
9.New York Coll Tradit Chinese Med Mineola, Mineola, NY 11501 USA

Chen, Jiayun,Gao, Peng,Xiao, Wei,et al. Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum[J]. DRUG RESISTANCE UPDATES,2023,70.

Chen, Jiayun.,Gao, Peng.,Xiao, Wei.,Cheng, Guangqing.,Krishna, Sanjeev.,...&Wang, Jigang.(2023).Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum.DRUG RESISTANCE UPDATES,70.

Chen, Jiayun,et al."Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum".DRUG RESISTANCE UPDATES 70(2023).