Molecular surveillance of Kelch 13 polymorphisms in Plasmodium falciparum isolates from Kenya and Ethiopia

Abstract

Background Timely molecular surveillance of Plasmodium falciparum kelch 13 (k13) gene mutations is essential for monitoring the emergence and stemming the spread of artemisinin resistance. Widespread artemisinin resistance, as observed in Southeast Asia, would reverse significant gains that have been made against the malaria burden in Africa. The purpose of this study was to assess the prevalence of k13 polymorphisms in western Kenya and Ethiopia at sites representing varying transmission intensities between 2018 and 2022. Methods Dried blood spot samples collected through ongoing passive surveillance and malaria epidemiological studies, respectively, were investigated. The k13 gene was genotyped in P. falciparum isolates with high parasitaemia: 775 isolates from four sites in western Kenya (Homa Bay, Kakamega, Kisii, and Kombewa) and 319 isolates from five sites across Ethiopia (Arjo, Awash, Gambella, Dire Dawa, and Semera). DNA sequence variation and neutrality were analysed within each study site where mutant alleles were detected. Results Sixteen Kelch13 haplotypes were detected in this study. Prevalence of nonsynonymous k13 mutations was low in both western Kenya (25/783, 3.19%) and Ethiopia (5/319, 1.57%) across the study period. Two WHO-validated mutations were detected: A675V in three isolates from Kenya and R622I in four isolates from Ethiopia. Seventeen samples from Kenya carried synonymous mutations (2.17%). No synonymous mutations were detected in Ethiopia. Genetic variation analyses and tests of neutrality further suggest an excess of low frequency polymorphisms in each study site. Fu and Li’s F test statistic in Semera was 0.48 (P > 0.05), suggesting potential population selection of R622I, which appeared at a relatively high frequency (3/22, 13.04%). Conclusions This study presents an updated report on the low frequency of k13 mutations in western Kenya and Ethiopia. The WHO-validated R622I mutation, which has previously only been reported along the north-west border of Ethiopia, appeared in four isolates collected from eastern Ethiopia. The rapid expansion of R622I across Ethiopia signals the need for enhanced monitoring of the spread of drug-resistant P. falciparum parasites in East Africa. Although ACT remains currently efficacious in the study areas, continued surveillance is necessary to detect early indicators of artemisinin partial resistance.

Evidence of Partial Artemisinin Resistance in Malaria Endemic Lake Region, Busia County, Western, Kenya

“…In Kenya, several novel and potential ART-R markers, including R539T, N458T, R561H, N431S, and A675V, have been detected in the malaria-endemic areas of the country [18,19]. However, most reported markers occur at low allelic frequencies.…”

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

“…2 Artemisinin combination therapies (ACT) have been instrumental in controlling the disease burden since their adoption as the first-line treatment in the early 2000s, 2,3 but this control is under threat with ACT treatment failure reported in South-East Asia and the Western Pacific (incidence summarized by region in the World Malaria report 2023). 1 Artemisinin-resistant P. falciparum has also been reported in Africa, 1,4,5 which is especially concerning as this region accounts for 94% of malaria cases globally. 1 Field surveillance measures that identify resistance to artemisinin derivatives and partner drugs to inform the adoption of different drug combinations are critical in the ongoing battle against drug resistance.…”

“…Artemisinin-resistant P. falciparum has also been reported in Africa, ,, which is especially concerning as this region accounts for 94% of malaria cases globally…”