Tropical medicine and health · 2026
Drug resistance gene polymorphisms of Plasmodium falciparum clinical isolates from Kinshasa, Democratic Republic of the Congo.
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Bitshi Mimie, Naruse Taeko K, Sakata-Kato Tomoyo, Mabi Héritier Nzuau, Kassanda Prince, Yakenvu Gloria Kangite, Tshibangu-Kabamba Evariste, Nkoli Papy Mandoko, Kaku Natsuko, Nakagama Yu, Kido Yasutoshi, Ngoyi Dieudonné Mumba, Kaneko Osamu
Аннотация
BACKGROUND: Sustained efficacy of artemisinin (ART)-based combination therapies is essential for controlling Plasmodium falciparum malaria in Africa. ART derivatives remain the key frontline treatment, while sulfadoxine-pyrimethamine is used for prevention. Recent detection in Africa of P. falciparum kelch 13 (k13) substitutions associated with ART resistance (ART-R), distinct from Southeast Asian k13 ART-R alleles, suggests local emergence. Together with widespread pyrimethamine resistance, ART-R poses a major public health concern. In the Democratic Republic of the Congo (DRC), however, data on resistance markers beyond conventional loci remain limited.
METHODS: From June 2022 to February 2023, 303 malaria rapid diagnostic test-positive patients with uncomplicated malaria were enrolled at three clinics in Kinshasa, the Democratic Republic of the Congo (DRC). Day 1 parasitemia reduction rate (PRR) after artemether-lumefantrine treatment was assessed by microscopy. The gene region encoding the K13 propeller domain was sequenced from 171 microscopy-confirmed P. falciparum cases. Whole-genome sequencing data from 31 culture-adapted isolates were used to examine polymorphisms and copy number in 13 resistance-associated genes: k13, coronin, kic4, kic5, kic7, px1, ap2-mu, ubp1, mdr1, mdr2, crt, dhfr, and dhps.
RESULTS: No validated or candidate K13 propeller mutation associated with ART partial resistance was detected, including in samples from patients with < 80% PRR. One isolate carried K13 A578S, a variant previously shown not to confer ART resistance. Whole-genome sequencing showed that all 13 genes were single copy and revealed diverse known and novel polymorphisms. K13 Asn-repeat variants and non-k13 candidate variants, including PX1 M1701I/D1705N, AP2-Mu S160N, and UBP1 E1528D, were detected. Partner-drug and antifolate markers included MDR1 Y184F, the CRT chloroquine-resistant IET haplotype, the DHFR N51I/C59R/S108N triple-mutant haplotype, and DHPS K540E. Among variants compared between PRR groups, the synonymous ap2-mu a300c substitution remained significant after false discovery rate correction.
CONCLUSIONS: Established K13 propeller-mediated ART partial resistance was not evident in Kinshasa at the time of sampling. However, diverse non-k13 candidate variants and persistent partner-drug and antifolate resistance markers support expanded molecular surveillance combined with clinical and ex vivo phenotypic monitoring.
METHODS: From June 2022 to February 2023, 303 malaria rapid diagnostic test-positive patients with uncomplicated malaria were enrolled at three clinics in Kinshasa, the Democratic Republic of the Congo (DRC). Day 1 parasitemia reduction rate (PRR) after artemether-lumefantrine treatment was assessed by microscopy. The gene region encoding the K13 propeller domain was sequenced from 171 microscopy-confirmed P. falciparum cases. Whole-genome sequencing data from 31 culture-adapted isolates were used to examine polymorphisms and copy number in 13 resistance-associated genes: k13, coronin, kic4, kic5, kic7, px1, ap2-mu, ubp1, mdr1, mdr2, crt, dhfr, and dhps.
RESULTS: No validated or candidate K13 propeller mutation associated with ART partial resistance was detected, including in samples from patients with < 80% PRR. One isolate carried K13 A578S, a variant previously shown not to confer ART resistance. Whole-genome sequencing showed that all 13 genes were single copy and revealed diverse known and novel polymorphisms. K13 Asn-repeat variants and non-k13 candidate variants, including PX1 M1701I/D1705N, AP2-Mu S160N, and UBP1 E1528D, were detected. Partner-drug and antifolate markers included MDR1 Y184F, the CRT chloroquine-resistant IET haplotype, the DHFR N51I/C59R/S108N triple-mutant haplotype, and DHPS K540E. Among variants compared between PRR groups, the synonymous ap2-mu a300c substitution remained significant after false discovery rate correction.
CONCLUSIONS: Established K13 propeller-mediated ART partial resistance was not evident in Kinshasa at the time of sampling. However, diverse non-k13 candidate variants and persistent partner-drug and antifolate resistance markers support expanded molecular surveillance combined with clinical and ex vivo phenotypic monitoring.