Plasmodium falciparum kelch 13 Mutations, 9 Countries in Africa, 2014-2018.
Ontology highlight
ABSTRACT:
SUBMITTER: Schmedes SE
PROVIDER: S-EPMC8237877 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Artemisinin resistance (AR) emerged in South East Asia 13 years ago and the identification of the resistance conferring molecular marker, Plasmodium falciparum Kelch 13 (Pfk13), 7 years ago has provided an invaluable tool for monitoring AR in malaria endemic countries. Molecular Pfk13 surveillance revealed the resistance foci in the Greater Mekong Subregion, an independent emergence in Guyana, South America, and a low frequency of mutations in Africa. The recent identification of the R561H Pfk13 AR associated mutation in Tanzania, Uganda and in Rwanda, where it has been associated with delayed parasite clearance, should be a concern for the continent. In this review, we provide a summary of Pfk13 resistance associated propeller domain mutation frequencies across Africa from 2012 to 2020, to examine how many other countries have identified these mutations. Only four African countries reported a recent identification of the M476I, P553L, R561H, P574L, C580Y and A675V Pfk13 mutations at low frequencies and with no reports of clinical treatment failure, except for Rwanda. These mutations present a threat to malaria control across the continent, since the greatest burden of malaria remains in Africa. A rise in the frequency of these mutations and their spread would reverse the gains made in the reduction of malaria over the last 20 years, given the lack of new antimalarial treatments in the event artemisinin-based combination therapies fail. The review highlights the frequency of Pfk13 propeller domain mutations across Africa, providing an up-to-date perspective of Pfk13 mutations, and appeals for an urgent and concerted effort to monitoring antimalarial resistance markers in Africa and the efficacy of antimalarials by re-establishing sentinel surveillance systems.
| S-EPMC8219943 | biostudies-literature
Project description:Artemisinin resistance, linked to polymorphisms in the Kelch gene on chromosome 13 of Plasmodium falciparum (k13), has outpaced containment efforts in South East Asia. For national malaria control programmes in the region, it is important to establish a surveillance system which includes monitoring for k13 polymorphisms associated with the clinical phenotype.Between February and December 2013, parasite clearance was assessed in 35 patients with uncomplicated P. falciparum treated with artesunate monotherapy followed by 3-day ACT in an isolated area on the Myanmar-Thai border with relatively low artemisinin drug pressure. Molecular testing for k13 mutations was performed on dry blood spots collected on admission.The proportion of k13 mutations in these patients was 41.7%, and only 5 alleles were detected: C580Y, I205T, M476I, R561H, and F446I. Of these, F446I was the most common, and was associated with a longer parasite clearance half-life (median) 4.1 (min-max 2.3-6.7) hours compared to 2.5 (min-max 1.6-8.7) in wildtype (p = 0·01). The prevalence of k13 mutant parasites was much lower than the proportion of k13 mutants detected 200 km south in a much less remote setting where the prevalence of k13 mutants was 84% with 15 distinct alleles in 2013 of which C580Y predominated.This study provides evidence of artemisinin resistance in a remote part of eastern Myanmar. The prevalence of k13 mutations as well as allele diversity varies considerably across short distances, presumably because of historical patterns of artemisinin use and population movements.
| S-EPMC5702082 | biostudies-other
Project description:BACKGROUND:Artemisinin-based combination therapy (ACT) is recommended at the initial phase for treatment of Plasmodium falciparum, to reduce morbidity and mortality in all countries where malaria is endemic. Polymorphism in portions of P. falciparum gene encoding kelch (K13)-propeller domains is associated with delayed parasite clearance after ACT. Of about 124 different non-synonymous mutations, 46 have been identified in Southeast Asia (SEA), 62 in sub-Saharan Africa (SSA) and 16 in both the regions. This is the first study designed to analyse the prevalence of polymorphism in the P. falciparum k13-propeller domain in the Jazan region of southwest Saudi Arabia, where malaria is endemic. METHODS:One-hundred and forty P. falciparum samples were collected from Jazan region of southwest Saudi Arabia at three different times: 20 samples in 2011, 40 samples in 2016 and 80 samples in 2020 after the implementation of ACT. Plasmodium falciparum kelch13 (k13) gene DNA was extracted, amplified, sequenced, and analysed using a basic local alignment search tool (BLAST). RESULTS:This study obtained 51 non-synonymous (NS) mutations in three time groups, divided as follows: 6 single nucleotide polymorphisms (SNPs) '11.8%' in samples collected in 2011 only, 3 (5.9%) in 2011and 2016, 5 (9.8%) in 2011 and 2020, 5 (9.8%) in 2016 only, 8 (15.7%) in 2016 and 2020, 14 (27.5%) in 2020 and 10 (19.6%) in all the groups. The BLAST revealed that the 2011 isolates were genetically closer to African isolates (53.3%) than Asian ones (46.7%). Interestingly, this proportion changed completely in 2020, to become closer to Asian isolates (81.6%) than to African ones (18.4%). CONCLUSIONS:Despite the diversity of the identified mutations in the k13-propeller gene, these data did not report widespread artemisinin-resistant polymorphisms in the Jazan region where these samples were collected. Such a process would be expected to increase frequencies of mutations associated with the resistance of ACT.
| S-EPMC7653757 | biostudies-literature
Project description:BackgroundTimely 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.MethodsDried 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.ResultsSixteen 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%).ConclusionsThis 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.
| S-EPMC10823687 | biostudies-literature
Project description:Malaria, an ancient mosquito-borne illness caused by Plasmodium parasites, is mostly treated with Artemisinin Combination Therapy (ACT). However, Single Nucleotide Polymorphisms (SNPs) mutations in the P. falciparum Kelch 13 (PfK13) protein have been associated with artemisinin resistance (ART-R). Therefore, this study aims to generate PfK13 recombinant proteins incorporating of two specific SNPs mutations, PfK13-V494I and PfK13-N537I, and subsequently analyze their binding interactions with artemisinin (ART). The recombinant proteins of PfK13 mutations and the Wild Type (WT) variant were expressed utilizing a standard protein expression protocol with modifications and subsequently purified via IMAC and confirmed with SDS-PAGE analysis and Orbitrap tandem mass spectrometry. The binding interactions between PfK13-V494I and PfK13-N537I propeller domain proteins ART were assessed through Isothermal Titration Calorimetry (ITC) and subsequently validated using fluorescence spectrometry. The protein concentrations obtained were 0.3 mg/ml for PfK13-WT, 0.18 mg/ml for PfK13-V494I, and 0.28 mg/ml for PfK13-N537I. Results obtained for binding interaction revealed an increased fluorescence intensity in the mutants PfK13-N537I (83 a.u.) and PfK13-V494I (143 a.u.) compared to PfK13-WT (33 a.u.), indicating increased exposure of surface proteins because of the looser binding between PfK13 protein mutants with ART. This shows that the PfK13 mutations may induce alterations in the binding interaction with ART, potentially leading to reduced effectiveness of ART and ultimately contributing to ART-R. However, this study only elucidated one facet of the contributing factors that could serve as potential indicators for ART-R and further investigation should be pursued in the future to comprehensively explore this complex mechanism of ART-R.
| S-EPMC11326563 | biostudies-literature
Project description:Objectives: In this study, we aimed to analyse the genetic diversity Kelch 13 (K13) propeller allele of the Plasmodium falciparum isolates mainly imported from Southeast Asia and Africa in southern China, including the provinces of Yunnan and Guangxi. Methods: At enrolment, we collected blood samples from patients with confirmed cases of malaria infection between January 2012 and December 2017, for analysis. Individual patient information was obtained via a malaria surveillance system. The malaria infections and P. falciparum K13 mutations were diagnosed by using a nested polymerase chain reaction (PCR) method. Results: The K13 mutations were identified in 283 P. falciparum isolates from 18 counties in Yunnan and 22 counties in Guangxi. Of Forty-six isolates (46/283, 16.3%) that harbored K13 mutant alleles were detected: 26.8% in Yunnan (33/123) and 8.1% in Guangxi (13/160). A total of 18 different K13 mutations were detected. Only the F446I mutation was detected in Yunnan isolates, and F446I was more frequent (20/46, 43.5%) than other alleles. Further, the temporal distribution of the F446I mutation ratio from 2012 to 2015 exhibited no significant difference in Yunnan Province (2012, 2/13, 15.4%; 2013, 7/40, 17.5%; 2014, 7/33, 21.2%; 2015, 4/37, 10.8%, p = 0.121). A578S allele was the main K13 mutation (5/283, 1.8%) from Africa. The K13 mutants were present in 33.3% of indigenous isolates, 27.4% of isolates from Southeast Asia, and 7.9% of isolates from Africa. The analysis of 10 neutral microsatellite loci of 60 isolates showed that at the TAA109 locus, the expected heterozygosity of F446I (H e = 0.112 ± 0.007) was much lower than that of wild type and other mutation types in Myanmar isolates. With respect to geographic distribution, TAA109 also exhibited a significant difference between isolates from Southeast Asia (H e = 0.139 ± 0.012) and those from Africa (H e = 0.603 ± 0.044). Conclusions: The present findings on the geographic diversity of K13 mutant alleles in P. falciparum may provide a basis for routine molecular surveillance and risk assessment, to monitor artemisinin resistance (ART) in China. Our results will be helpful for enriching the artemisinin resistance database in China during the elimination and post-elimination phases.
| S-EPMC6491575 | biostudies-literature
Project description:Delayed clearance of Plasmodium falciparum by artemisinin-based combination therapies (ACTs) has already been observed for African isolates. Here, we aimed to investigate the prevalence, among travelers returning from African countries, of polymorphisms in two genes correlated with delayed parasite clearance (encoding P. falciparum Kelch 13 [PfK13] and ubiquitin-specific protease 1 [pfubp1]) reported in eastern China and to provide baseline data for antimalarial drug resistance (ART) surveillance and evaluation. A total of 153 filter paper blood spots collected in 2017-2019 from patients with uncomplicated P. falciparum cases in Anhui and Shandong Provinces were included in this study. Among them, 3.3% (5/153) of the isolates carried PfK13 mutations, and 3 of them harbored the same synonymous mutation, C469C. A total of 13.1% (20/153) of the isolates were found to contain pfubp1 mutations, and all were nonsynonymous. The pfubp1 genotypes associated with ART that occurred in this study included E1528D (6.5% [10/153]) and D1525E (2.6% [4/153]). However, a high prevalence of the previously unreported mutation E1531D (5.9% [9/153]) was also detected. In addition, two types of deletions (encoding KID and KIE, respectively) and two types of insertions (encoding KYE and KYDKYD, respectively) were found in 16 isolates and 6 isolates, respectively. This study showed limited variation in PfK13 among travelers returning from African countries and suggested other potential molecular markers, such as pfubp1, for use in the surveillance of African isolates in ACT susceptibility studies. Further clinical trial research is under way to investigate these PfK13 and pfubp1 mutations, as well as other candidate molecular markers, and their roles in delaying parasite clearance.
| S-EPMC7577147 | biostudies-literature
Project description:Artemisinin-based combination therapy (ACT) offers highly successful treatment of malaria. Emergence and spread of Plasmodium falciparum (Pf) parasites with decreased susceptibility to ACT in South-East Asia has caused concern worldwide. The current accepted criteria to assess artemisinin (ART) resistance relies upon data on treatment failure, delayed parasite clearance at day 3 (DPC3), parasite clearance half-life (PCHL) and in-vitro/ex-vivo ring stage survival assays (RSAs). Interestingly, some studies suggest that DPC3 does not provide a distinct separation between ART sensitive/resistant strains, and RSA differences may also be inconclusive. More recently, recrudescence of ART treated Pf, independent of the presence of Kelch 13 (K13) mutation (C580Y), has been reported in the monkey malaria model suggesting that genes other than K13 like coronin, dhps, dhfr, crt, mdr1 and plasmepsin1 may contribute towards ACT failure. Here we have collated the distribution of K13 mutants from Pf strains in South Asia. A total of fifty Pf-K13 mutations have been studied for ART resistance in South Asia of which nine have been validated while eleven are potentials for ART resistance. The remaining thirty K13 mutations have been reported from various locations in South Asia but lack corroborative clinical data on ART resistance/ACT failure. Of the fifty, fourteen K13 mutations have been identified in India including four novel mutations (S549Y, G625R, N657H, D702N). Structural mapping of these K13 mutations does not offer any coherent explanation for their contribution towards ART resistance as they are scattered in the K13 structure. Thus, K13 mutations likely provide only a partial synopsis, and we propose that all suspect cases of ACT failure be assessed by: 1) DPC3, 2) PCHL, 3) in-vitro/ex-vivo RSAs and 4) GWAS data in an effort to annotate the resistance status of the parasites. These efforts may help in surveillance and containment of ART resistance/ACT failure in South Asia.
| S-EPMC6796718 | biostudies-literature
Project description:We determined the prevalence of Kelch 13 mutations and pfmdr1 copy number in samples collected from the Thailand-Myanmar border, the Thailand-Cambodia border, and southern Thailand from 2002 to 2007. C580Y was the most prevalent in Trat (Thailand-Cambodia border) and Ranong (Thailand-Myanmar border) at 42% (24/57) and 13% (6/48), respectively. Less predominant mutations were also identified including R539T (7%, 4/57) and Y493H (2%, 1/57) in Trat, P574L (6%, 3/48) and P553L (2%, 1/48) in Ranong, and N537I and D452E (7%, 1/15) in Sangkhlaburi (Thailand-Myanmar border). Samples from Mae sot (33%, 11/33) harbored the highest percentage of multiple pfmdr1 copies, followed by Trat (18%, 10/57), Chiang Dao in 2003 (13%, 4/30), Phang Nga (5%, 2/44), and Chiang Dao in 2002 (4%, 1/26). This retrospective study provides geographic diversity of K13 and pfmdr1 copies and the emergence of these molecular markers in Thailand, an important background information for future surveillance in the region.
| S-EPMC8592159 | biostudies-literature
Project description:The emergence of artemisinin-resistant Plasmodium falciparum parasites in Southeast Asia threatens malaria control and elimination. The interconnectedness of parasite populations may be essential to monitor the spread of resistance. Combining a published barcoding system of geographically restricted single-nucleotide polymorphisms (SNPs), mainly mitochondria of P. falciparum with SNPs in the K13 artemisinin resistance marker, could elucidate the parasite population structure and provide insight regarding the spread of drug resistance. We explored the diversity of mitochondrial SNPs (bp position 611-2825) and identified K13 SNPs from malaria patients in the districts of India (Ranchi), Tanzania (Korogwe), and Senegal (Podor, Richard Toll, Kaolack, and Ndoffane). DNA was amplified using a nested PCR and Sanger-sequenced. Overall, 199 K13 sequences (India: N = 92; Tanzania: N = 48; Senegal: N = 59) and 237 mitochondrial sequences (India: N = 93; Tanzania: N = 48; Senegal: N = 96) were generated. SNPs were identified by comparisons with reference genomes. We detected previously reported geographically restricted mitochondrial SNPs (T2175C and G1367A) as markers for parasites originating from the Indian subcontinent and several geographically unrestricted mitochondrial SNPs. Combining haplotypes with published P. falciparum mitochondrial genome data suggested possible regional differences within India. All three countries had G1692A, but Tanzanian and Senegalese SNPs were well-differentiated. Some mitochondrial SNPs are reported here for the first time. Four nonsynonymous K13 SNPs were detected: K189T (India, Tanzania, Senegal); A175T (Tanzania); and A174V and R255K (Senegal). This study supports the use of mitochondrial SNPs to determine the origin of the parasite and suggests that the P. falciparum populations studied were susceptible to artemisinin during sampling because all K13 SNPs observed were outside the propeller domain for artemisinin resistance.
| S-EPMC8592148 | biostudies-literature