Decreased
            <i>In Vitro</i>
            Artemisinin Sensitivity of
            <i>Plasmodium falciparum</i>
            across India

Chakrabarti, Rimi; White, John; Babar, Prasad H.; Kumar, Sanjiv; Mudeppa, Devaraja G.; Mascarenhas, Anjali; Pereira, Ligia; Dash, Rashmi; Maki, Jennifer; Sharma, Ambika; Gogoi, Kabita; Sarma, Devojit Kumar; Bhowmick, Ipsita Pal; Manoharan, Suresh Kumar; Gomes, Edwin; Mahanta, Jagadish; Mohapatra, Pradyumna K.; Chéry, Lisly; Rathod, Pradipsinh K.

doi:10.1128/aac.00101-19

Cited by 17 publications

(20 citation statements)

References 48 publications

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“…The NN insert between codons 141 and 142 of Pfk13 reported here is the first of its kind seen in Senegal (Table 1). However, insertions between codons 142 and 143 have previously been reported in India [30] and insertions at codon 142 of Pfk13 have been reported in isolates from Senegal [29] and Cambodia [31]. The T149S mutation detected here in Kédougou was also previously reported in Dakar [29].…”

Section: Discussionsupporting

confidence: 72%

Amplicon deep sequencing of kelch13 in Plasmodium falciparum isolates from Senegal

Gaye

Ndiaye

et al. 2020

Malar J

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Background: In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy (ACT) with artemether-lumefantrine as the first-line treatment for uncomplicated Plasmodium falciparum malaria. To date, multiple mutations associated with artemisinin delayed parasite clearance have been described in Southeast Asia in the Pfk13 gene, such as Y493H, R539T, I543T and C580Y. Even though ACT remains clinically and parasitologically efficacious in Senegal, the spread of resistance is possible as shown by the earlier emergence of resistance to chloroquine in Southeast Asia that subsequently spread to Africa. Therefore, surveillance of artemisinin resistance in malaria endemic regions is crucial and requires the implementation of sensitive tools, such as next-generation sequencing (NGS) which can detect novel mutations at low frequency. Methods: Here, an amplicon sequencing approach was used to identify mutations in the Pfk13 gene in eighty-one P. falciparum isolates collected from three different regions of Senegal. Results: In total, 10 SNPs around the propeller domain were identified; one synonymous SNP and nine non-synonymous SNPs, and two insertions. Three of these SNPs (T478T, A578S and V637I) were located in the propeller domain. A578S, is the most frequent mutation observed in Africa, but has not previously been reported in Senegal. A previous study has suggested that A578S could disrupt the function of the Pfk13 propeller region. Conclusion: As the genetic basis of possible artemisinin resistance may be distinct in Africa and Southeast Asia, further studies are necessary to assess the new SNPs reported in this study.

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Section: Discussionsupporting

confidence: 72%

Amplicon deep sequencing of kelch13 in Plasmodium falciparum isolates from Senegal

Gaye

Ndiaye

et al. 2020

Malar J

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“…falciparum by using ring stage survival assay demanding a future investigation on the potential change in the ACT effectiveness in P . falciparum parasites from NE India 29 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of drug resistance and genetic diversity of Plasmodium falciparum parasites from Tripura, Northeast India

Patgiri

Sarma

Sarmah

et al. 2019

Sci Rep

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Monitoring of anti-malarial drug resistance is vital in Northeast India as this region shares its international border with Southeast Asia. Genetic diversity of Plasmodium parasites regulates transmission dynamics, disease severity and vaccine efficacy. P. falciparum chloroquine resistance transporter (Pfcrt), multidrug resistance-1 (Pfmdr-1) and kelch 13 propeller (PfK-13) genes which govern antimalarial drug resistance and three genetic diversity markers, merozoite surface protein 1 and 2 (Pfmsp-1, Pfmsp-2) and glutamate rich protein (Pfglurp) were evaluated from Tripura, Northeast India using molecular tools. In the Pfcrt gene, 87% isolates showed triple mutations at codons M74I, N75E and K76T. 12.5% isolates in Pfmdr-1 gene showed mutation at N86Y. No polymorphism in PfK-13 propeller was found. Polyclonal infections were observed in 53.85% isolates and more commonly in adults (p = 0.0494). In the Pfmsp-1 locus, the K1 allelic family was predominant (71.2%) followed by the 3D7/IC family (69.2%) in the Pfmsp-2 locus. RII region of Pfglurp exhibited nine alleles with expected heterozygosity of 0.85. The multiplicity of infection for Pfmsp-1, Pfmsp-2 and Pfglurp were 1.56, 1.31 and 1.06 respectively. Overall, the study demonstrated a high level of chloroquine resistance and extensive parasite diversity in the region, necessitating regular surveillance in this population group.

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“…While Das et al emphasize that the criteria required to define ART resistance are met, the points raised by the malaria research community in India are also valid (Rasmussen et al, 2019). Intriguingly, another study from India by Chakrabarti et al in 2019 showed reduced sensitivity to DHA (Chakrabarti et al, 2019). Further to this, the authors reported A675V mutation within the Kelch propeller domain (RSA of 2%).…”

Section: Landscape Of K13 Mutationsmentioning

confidence: 98%

Profiles of Kelch mutations in Plasmodium falciparum across South Asia and their implications for tracking drug resistance

Chhibber‐Goel

Sharma

2019

International Journal for Parasitology: Drugs and Drug Resistan

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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.

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Decreased In Vitro Artemisinin Sensitivity of Plasmodium falciparum across India

Cited by 17 publications

References 48 publications

Amplicon deep sequencing of kelch13 in Plasmodium falciparum isolates from Senegal

Amplicon deep sequencing of kelch13 in Plasmodium falciparum isolates from Senegal

Characterization of drug resistance and genetic diversity of Plasmodium falciparum parasites from Tripura, Northeast India

Profiles of Kelch mutations in Plasmodium falciparum across South Asia and their implications for tracking drug resistance

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