Plasmodium falciparum Kelch Propeller Polymorphisms in Clinical Isolates from Ghana from 2007 to 2016

Abstract

The continuous surveillance of polymorphisms in the kelch propeller domain of Plasmodium falciparum from Africa is important for the discovery of the actual markers of artemisinin resistance in the region. The information on the markers is crucial for control strategies involving chemotherapy and chemoprophylaxis for residents and nonimmune travelers to the country. Polymorphisms in the kelch propeller domain of Ghanaian malaria parasites from three different ecological zones at several time periods were assessed. A total of 854 archived samples (2007 to 2016) collected from uncomplicated malaria patients aged ≤9 years old from 10 sentinel sites were used. Eighty-four percent had wild-type sequences (PF3D7_1343700), while many of the mutants had mostly nonsynonymous mutations clustered around codons 404 to 650. Variants with different amino acid changes of the codons associated with artemisinin (ART) resistance validated markers were observed in Ghanaian isolates: frequencies for I543I, I543S, I543V, R561P, R561R, and C580V were 0.12% each and 0.6% for R539I. Mutations reported from African parasites, A578S (0.23%) and Q613L (0.23%), were also observed. Three persisting nonsynonymous (NS) mutations, N599Y (0.005%), K607E (0.004%), and V637G (0.004%), were observed in 3 of the 5 time periods nationally. The presence of variants of the validated markers of artemisinin resistance as well as persisting polymorphisms after 14 years of artemisinin-based combination therapy use argues for continuous surveillance of the markers. The molecular markers of artemisinin resistance and the observed variants will be monitored subsequently as part of ongoing surveillance of antimalarial drug efficacy/resistance studies in the country.

Antimalarial Drug Resistance Profiling of Plasmodium falciparum Infections in Ghana Using Molecular Inversion Probes and Next-Generation Sequencing

“…None of the artemisinin resistance-associated pfk13 mutations observed in Southeast Asia (M476I, Y493H, R539T, I543T, and C580Y) were observed in the sample set. Our study identified the nonsynonymous pfk13 propeller mutations (C532S, S522C, P553T, and Q613H) that have previously been reported to be variants in Africa (28,(44)(45)(46)(47) at low frequencies, as well as some new mutations (Table S5). There were no temporal trends.…”

Characterization of putative drug resistant biomarkers in Plasmodium falciparum isolated from Ghanaian blood donors

“…Malaria endemic regions that have previously identified A578S, must enhance surveillance for C580Y allele. Matrevi et al [23] have also detected C580V (very close allele of C580Y) in Central region of Ghana. Furthermore, Feng et al [41] in 2013 also detected three isolates of C580Y SNP in Chinese migrant workers from Ghana.…”

“…Kelch 13 A578S allele, as was observed in this study, has also been previously detected in Ghanaian parasite isolates. In Ghana, A578S has been previously identified in three regions, Eastern, Bono (formerly Brong Ahafo) and in the Upper West Regions [23]. The A578S allele is two codons away from C580Y allele.…”

“…In previous studies in Ghana, high frequencies of mutation in Pfcrt, Pfmdr1, Pfdhfr and Pfdhps were identified in P. falciparum infected children aged 4-15 years [22,23]. However, such study is yet to done in Ghanaian adults and for that matter, blood donors.…”

Assessment of antimalarial drug resistant markers in asymptomatic Plasmodium falciparum infections after 4 years of indoor residual spraying in Northern Ghana

“…Furthermore, the critical pfk13 gene mutation C580Y, which is associated with delayed clearance of ART in Southeast Asia [35,[90][91][92], was not detected across any of the time points. Similarly, the other 8 validated Southeast Asian K13 alleles associated with ART resistance (F446I, N458Y/I, M476I/V, Y493H, R539T, I543T, P553L, R561H), are also rare in Africa [93,94]. The African K13 mutant alleles (including G449A/D, V520A, S522C, C542Y, G544R, G545E, A557S, R561C, A578S, A617V/T, V637A/I/D, G638R) either do not show evidence of selection in the parasite population or have not yet been associated with clinical artemisinin resistance [37,90,94,95].…”