Abstract
Malaria is one of the deadliest parasitic diseases in human. Currently, Artemisinin-based combination therapy is considered as the gold standard and most common treatment option. However, the origin and transmission of Plasmodium falciparum from the Greater Mekong Subregion, which has decreased artemisinin (ART) sensitivity, has sparked global concern. The reduced ART sensitivity has been associated with mutations in the Atpase6 and Kelch13 propeller domain of Plasmodium falciparum. A molecular marker is critically needed to monitor the spread of artemisinin resistance. In this article, we reviewed the k13 mutations and potential marker for ART resistance in India. There have been fourteen mutations identified, three of which have been validated by the World Health Organization (WHO) as artemisinin resistance mutations (F446I, R561H/C, and R539T). Among them, the role of F446I and R561H/C in ART resistance is conflicting. R539T and G625R mutation has been identified as an ART- resistance marker in India.
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Source: NVBDCP and reported k-13 validated mutations
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Abubakar UF, Adam R, Mukhtar MM, Muhammad A, Yahuza AA, Ibrahim SS (2020) Identification of mutations in antimalarial resistance gene kelch13 from Plasmodium falciparum Isolates in Kano. Nigeria Trop Med Infect Dis 5(2):85. https://doi.org/10.3390/tropicalmed5020085
Ahmed A, Bararia D, Vinayak S, Yameen M, Biswas S, Dev V, Kumar A, Ansari MA, Sharma YD (2004) Plasmodium falciparum Isolates in India exhibit a progressive increase in mutations associated with sulfadoxine-pyrimethamine resistance. Antimicrob Agents Chemother 48(3):879–889. https://doi.org/10.1128/AAC.48.3.879-889.2004
Ansari HR, Templeton TJ, Subudhi AK, Ramaprasad A, Tang J, Lu F, Naeem R, Hashish Y, Oguike MC, Benavente ED, Clark TG, Sutherland CJ, Barnwell JW, Culleton R, Cao J, Pain A (2016) Genome-scale comparison of expanded gene families in Plasmodium ovale wallikeri and Plasmodium ovale curtisi with Plasmodium malariae and with other Plasmodium species. Int J Parasitol 46(11):685–696. https://doi.org/10.1016/j.ijpara.2016.05.009
Antinori S, Galimberti L, Milazzo L, Corbellino M (2013) Plasmodium knowlesi: the emerging zoonotic malaria parasite. Acta Trop 125(2):191–201. https://doi.org/10.1016/j.actatropica.2012.10.008
Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, Kim S, Duru V, Bouchier C, Ma L, Lim P, Leang R, Duong S, Sreng S, Suon S, Chuor CM, Bout DM, Ménard S, Rogers WO (2014) A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505:50–55. https://doi.org/10.1038/nature12876
Barik T (2015) Antimalarial drug: from its development to deface. Curr Drug Discov Technol 12(4):225–228. https://doi.org/10.2174/1570163812666150907100019
Bridgford JL, Xie SC, Cobbold SA, Pasaje CFA, Herrmann S, Yang T, Gillett DL, Dick LR, Ralph SA, Dogovski C, Spillman NJ, Tilley L (2018) Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome. Nat Commun 9(1):1–9. https://doi.org/10.1038/s41467-018-06221-1
Bwire GM, Ngasala B, Mikomangwa WP, Kilonzi M, Kamuhabwa AAR (2020) Detection of mutations associated with artemisinin resistance at k13-propeller gene and a near-complete return of chloroquine susceptible falciparum malaria in Southeast of Tanzania. Sci Rep 10(1):1–7. https://doi.org/10.1038/s41598-020-60549-7
Chaturvedi N, Bhandari S, Bharti PK, Basak SK, Singh MP, Singh N (2015) Sympatric distribution of Plasmodium ovale curtisi and P. ovale wallikeri in India: implication for the diagnosis of malaria and its control. Trans R Soc Trop Med Hyg 109(5):352–354
Chen N, Kyle DE, Pasay C, Fowler EV, Baker J, Peters JM, Cheng Q (2003) pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum Isolates from the Philippines. Antimicrob Agents Chemother 47(11):3500–3505. https://doi.org/10.1128/AAC.47.11.3500-3505.2003
Codd A, Teuscher F, Kyle DE, Cheng Q, Gatton ML (2011) Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure. Malar J 10(1):56. https://doi.org/10.1186/1475-2875-10-56
Das M, Kalita M, Chetry S, Dutta P (2017) K13 Kelch Propeller domain and mdr1 sequence polymorphism in field isolates from northeast region. India Hum Parasit Dis. https://doi.org/10.1177/1179570017706870
Das S, Manna S, Saha B, Hati AK, Roy S (2019) Novel pfkelch13 gene polymorphism associates with artemisinin resistance in Eastern India. Clin Infect Dis 69(7):1144–1152. https://doi.org/10.1093/cid/ciy1038
Das S, Saha B, Hati AK, Roy S (2018) Evidence of artemisinin-resistant Plasmodium falciparum Malaria in Eastern India. N Engl J Med 379(20):1962–1964. https://doi.org/10.1056/NEJMc1713777
Draper SJ, Sack BK, King CR, Nielsen CM, Rayner JC, Higgins MK, Long CA, Seder RA (2018) Malaria vaccines: recent advances and new horizons. Cell Host Microbe 24(1):43–56. https://doi.org/10.1016/j.chom.2018.06.008
Dwivedi A, Khim N, Reynes C, Ravel P, Ma L, Tichit M, Bourchier C, Kim S, Dourng D, Khean C, Chim P, Siv S, Frutos R, Lek D, Mercereau-Puijalon O, Ariey F, Menard D, Cornillot E (2016) Plasmodium falciparum parasite population structure and gene flow associated to anti-malarial drugs resistance in Cambodia. Malar J. https://doi.org/10.1186/s12936-016-1370-y
Escobar C, Pateira S, Lobo E, Lobo L, Teodosio R (2015) Polymorphisms in Plasmodium falciparum K13-Propeller in Angola and mozambique after the introduction of the ACTs. PLoS ONE 10(3):e0119215. https://doi.org/10.1371/journal.pone.0119215
Fairhurst RM (2015) Understanding artemisinin-resistant malaria: what a difference a year makes. Curr Opin Infect Dis 28(5):417–425. https://doi.org/10.1097/QCO.0000000000000199
Feng J, Zhou D, Lin Y, Xiao H, Yan H, Xia Z (2015) Amplification of pfmdr1, pfcrt, pvmdr1, and K13 propeller polymorphisms associated with Plasmodium falciparum and Plasmodium vivax isolates from the China-Myanmar border. Antimicrob Agents Chemother 59(5):2554–2559
Hawkes M, Conroy AL, Opoka RO, Namasopo S, Zhong K, Liles WC, John CC, Kain KC (2015) Slow Clearance of Plasmodium falciparum in Severe Pediatric Malaria, Uganda, 2011–2013. Emerg Infect Dis 21(7):1237–1239. https://doi.org/10.3201/eid2107.150213
Joste V, Kamaliddin C, Kendjo E, Hubert V, Argy N, Houzé S (2018) Distinction of Plasmodium ovale wallikeri and Plasmodium ovale curtisi using quantitative Polymerase Chain Reaction with High Resolution Melting revelation. Sci Rep 8(1):1–8. https://doi.org/10.1038/s41598-017-18026-1
Kamau E, Campino S, Amenga-Etego L, Drury E, Ishengoma D, Johnson K, Mumba D, Kekre M, Yavo W, Mead D, Bouyou-Akotet M, Apinjoh T, Golassa L, Randrianarivelojosia M, Andagalu B, Maiga-Ascofare O, Amambua-Ngwa A, Tindana P, Ghansah A (2015) K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. J Infect Dis 211(8):1352–1355. https://doi.org/10.1093/infdis/jiu608
Kheang ST, Sovannaroth S, Ek S, Chy S, Chhun P, Mao S, Nguon S, Lek DS, Menard D, Kak N (2017) Prevalence of K13 mutation and Day-3 positive parasitemia in an artemisinin-resistant malaria-endemic area of Cambodia: A cross-sectional study. Malar J. https://doi.org/10.1186/s12936-017-2024-4
Kumar A, Moirangthem R, Gahlawat SK, Chandra J, Gupta P, Valecha N, Anvikar A, Singh V (2015) Emergence of sulfadoxine-pyrimethamine resistance in Indian isolates of Plasmodium falciparum in the last two decades. Infect Genet Evol 36:190–198. https://doi.org/10.1016/j.meegid.2015.08.027
Lalremruata A, Jeyaraj S, Engleitner T, Joanny F, Lang A, Bélard S, Mombo-Ngoma G, Ramharter M, Kremsner PG, Mordmüller B, Held J (2017) Species and genotype diversity of Plasmodium in malaria patients from Gabon analyzed by next-generation sequencing. Malar J. https://doi.org/10.1186/s12936-017-2044-0
Laminou I, Lamine M, Arzika I, Mahamadou B, Gora D, Dieye A (2018) Detection of Plasmodium falciparum K13 Propeller A569G mutation after artesunate-amodiaquine treatment failure in Niger. J Adv Biol Biotechnol 18(2):1–8. https://doi.org/10.9734/jabb/2018/42872
Li Qigui, Hickman M (2015) The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug-Resistant Parasites. In Ahmed T A (ed) Basic Pharmacokinetic Concepts and Some Clinical Applications, 1st eds. Intech Open, Janeza trdine, pp. 1–32
Lon CT, Tsuyuoka R, Phanouvong S, Nivanna N, Socheat D, Sokhan C, Blum N, Christophel EM, Smine A (2006) Counterfeit and substandard antimalarial drugs in Cambodia. Trans R Soc Trop Med Hyg 100(11):1019–1024. https://doi.org/10.1016/j.trstmh.2006.01.003
Mishra N, Bharti RS, Mallick P, Singh OP, Srivastava B, Rana R, Phookan S, Gupta HP, Ringwald P, Valecha N (2016) Emerging polymorphisms in falciparum Kelch 13 gene in Northeastern region of India. Malar J. https://doi.org/10.1186/s12936-016-1636-4
Mishra N, Kaitholia K, Srivastava B, Shah NK, Narayan JP, Dev V, Phookan S, Anvikar AR, Rana R, Bharti RS, Sonal GS (2014) Declining efficacy of artesunate plus sulphadoxine-pyrimethamine in northeastern India. Malar J. https://doi.org/10.1186/1475-2875-13-284
Mishra N, Prajapati SK, Kaitholia K, Bharti RS, Srivastava B, Phookan S, Anvikar AR, Dev V, Sonal GS, Dhariwal AC, White NJ, Valecha N (2015) Surveillance of artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker. Antimicrob Agents Chemother 59(5):2548–2553. https://doi.org/10.1128/AAC.04632-14
Mishra S, Bharti PK, Shukla MM, Ali NA, Kashyotia SS, Kumar A, Dhariwal AC, Singh N (2017) Clinical and molecular monitoring of Plasmodium falciparum resistance to antimalarial drug (artesunate+sulphadoxine-pyrimethamine) in two highly malarious districts of Madhya Pradesh, Central India from 2012–2014. Pathog Glob Health 111(4):186–194. https://doi.org/10.1080/20477724.2017.1331875
Müller O, Lu GY, Von Seidlein L (2019) Geographic expansion of artemisinin resistance. J Travel Med. https://doi.org/10.1093/jtm/taz030
Murmu LK, Sahu AA, Barik TK (2021) Diagnosing the drug resistance signature in Plasmodium falciparum: a review from contemporary methods to novel approaches. J Parasit Dis. https://doi.org/10.1007/s12639-020-01333-2
Nyunt MH, Hlaing T, Oo HW, Tin-Oo LLK, Phway HP, Wang B, Zaw NN, Han SS, Tun T, San KK, Kyaw MP, Han ET (2015) Molecular assessment of artemisinin resistance markers, polymorphisms in the K13 propeller, and a multidrug-resistance gene in the Eastern and Western Border Areas of Myanmar. Clin Infect Dis 60(8):1208–1215. https://doi.org/10.1093/cid/ciu1160
Nyunt MH, Soe MT, Myint HW, Oo HW, Aye MM, Han SS, Zaw NN, Cho C, Aung PZ, Kyaw KT, Aye TT, San NA, Ortega L (2017) Clinical and molecular surveillance of artemisinin-resistant falciparum malaria in Myanmar (2009–2013). Malar J. https://doi.org/10.1186/s12936-017-1983-9
Nzoumbou-Boko R, Panté-Wockama CBG, Ngoagoni C, Petiot N, Legrand E, Vickos U, Gody JC, Manirakiza A, Ndoua C, Lombart JP, Ménard D (2020) Molecular assessment of kelch13 non-synonymous mutations in Plasmodium falciparum isolates from Central African Republic (2017–2019). Malar J. https://doi.org/10.1186/s12936-020-03264-y
Oguike MC, Betson M, Burke M, Nolder D, Stothard JR, Kleinschmidt I, Proietti C, Bousema T, Ndounga M, Tanabe K, Ntege E, Culleton R, Sutherland CJ (2011) Plasmodium ovale curtisi and Plasmodium ovale wallikeri circulate simultaneously in African communities. Int J Parasitol 41(6):677–683. https://doi.org/10.1016/j.ijpara.2011.01.004
Ouattara A, Kone A, Adams M, Fofana B, Maiga AW, Hampton S, Coulibaly D, Thera MA, Diallo N, Dara A, Sagara I, Gil JP, Bjorkman A, Takala-Harrison S, Doumbo OK, Plowe CV, Djimde AA (2015) Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara. Mali Am J Trop Med Hyg 92(6):1202–1206. https://doi.org/10.4269/ajtmh.14-0605
Packard RM (2014) The origins of antimalarial-drug resistance. N Engl J Med 371:397–399. https://doi.org/10.1056/NEJMp1403340
Payne D (1987) Spread of chloroquine resistance in Plasmodium falciparum. Parasitol Today 3(8):241–246. https://doi.org/10.1016/0169-4758(87)90147-5
Putaporntip C, Kuamsab N, Kosuwin R, Tantiwattanasub W, Vejakama P, Sueblinvong T, Seethamchai S, Jongwutiwes S, Hughes AL (2016) Natural selection of K13 mutants of Plasmodium falciparum in response to artemisinin combination therapies in Thailand. Clin Microbiol Infect 22(3):285.e1-285.e8. https://doi.org/10.1016/j.cmi.2015.10.027
Sehgal PN, Sharma MTD, Sharma SL et al (1973) Resistance to chloroquine in falciparum malaria in Assam state. India J Commun Dis 5:175–180
Sinclair D, Zani B, Donegan S, Olliaro P, Garner P (2009) Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD007483.pub2
Somé AF, Sorgho H, Zongo I, Bazié T, Nikiéma F, Sawadogo A, Zongo M, Compaoré Y, Ouédraogo J (2016) Polymorphisms in K13, pfcrt, pfmdr1, pfdhfr, and pfdhps in parasites isolated from symptomatic malaria patients in Burkina Faso. Parasite. https://doi.org/10.1051/parasite/2016069
Sharma YD, Biswas S, Pillai CR, Ansari MA, Adak T, Devi CU (1996) High prevalence of chloroquine resistant Plasmodium falciparum infection in the Rajasthan epidemic. Acta Trop 62(3):135–141. https://doi.org/10.1016/S0001-706X(96)00031-9
Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, Dacheux M, Khim N, Zhang L, Lam S, Gregory PD, Urnov FD, Mercereau-Puijalon O, Benoit-Vical F, Fairhurst RM, Ménard D, Fidock DA (2015) K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 347(6220):428–431. https://doi.org/10.1126/science.1260867
Talundzic E, Okoth SA, Congpuong K, Plucinski MM, Morton L, Goldman IF, Kachur PS, Wongsrichanalai C, Satimai W, Barnwell JW, Udhayakumar V (2015) Selection and spread of artemisinin-resistant alleles in thailand prior to the global artemisinin resistance containment campaign. PLoS Pathog 11(4):e1004862. https://doi.org/10.1371/journal.ppat.1004789
Taylor SM, Parobek CM, De Conti DK, Kayentao K, Coulibaly SO, Greenwood BM, Tagbor H, Williams J, Bojang K, Njie F, Desai M, Kariuki S, Gutman J, Mathanga DP, Mårtensson A, Ngasala B, Conrad MD, Rosenthal PJ, Tshefu AK et al (2014) Absence of putative artemisinin resistance mutations among Plasmodium falciparum in sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis 211(5):680–688. https://doi.org/10.1093/infdis/jiu467
Tse EG, Korsik M, Todd MH (2019) The past, present, and future of anti-malarial medicines. Malar J. https://doi.org/10.1186/s12936-019-2724-z
Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, Lin K, Kyaw MP, Plewes K, Faiz MA, Dhorda M, Cheah PY, Pukrittayakamee S, Ashley EA, Anderson TJC, Nair S, McDew-White M, Flegg JA, Grist EPM et al (2015) Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: A cross-sectional survey of the K13 molecular marker. Lancet Infect Dis 15(4):415–421. https://doi.org/10.1016/S1473-3099(15)70032-0
Vinayak S, Biswas S, Dev V, Kumar A, Ansari MA, Sharma YD (2003) Prevalence of the K76T mutation in the pfcrt gene of Plasmodium falciparum among chloroquine responders in India. Acta Trop 87(2):287–293. https://doi.org/10.1016/S0001-706X(03)00021-4
Wang Z, Wang Y, Cabrera M, Zhang Y, Gupta B, Wu Y, Kemirembe K, Hu Y, Liang X, Brashear A, Shrestha S, Li X, Miao J, Sun X, Yang Z, Cui L (2015) Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene. Antimicrob Agents Chemother 59(11):6952–6959. https://doi.org/10.1128/AAC.01255-15
Witkowski B, Menard D, Amaratunga C, Fairhurst R (2013a) Ring stage Survival Assays (RSA) to evaluate the in vitro and ex vivo susceptibility of Plasmodium falciparum to artemisinins. Institute Pasteur du Cambodge- National Institutes of Health Procedure RSAv1
Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, Lim P, Mao S, Fairhurst RM, Menard D (2013b) Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis 13(12):1043–1049. https://doi.org/10.1016/S1473-3099(13)70252-4
Woodrow CJ, White NJ (2017) The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread. Microbiol Rev 41(1):34–48. https://doi.org/10.1093/femsre/fuw037
WHO (2018) Artemisinin resistance and artemisinin-based combination therapy efficacy. https://www.who.int/malaria/publications/atoz/artemisinin-resistance-august2018/en/. Accessed 12 Oct 2020
WHO (2019) World Malaria Report 2019. https://www.who.int/publications-detail/world-malaria-report-2019. Accessed 12 Oct 2020
Wykes MN (2013) Why haven’t we made an efficacious vaccine for malaria? EMBO Rep 14:661. https://doi.org/10.1038/embor.2013.103
Ye R, Hu D, Zhang Y, Huang Y, Sun X, Wang J, Chen X, Zhou H, Zhang D, Mungthin M, Pan W (2016) Distinctive origin of artemisinin-resistant Plasmodium falciparum on the China-Myanmar border. Sci Rep. https://doi.org/10.1038/srep20100
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Murmu, L.K., Barik, T.K. An analysis of Plasmodium falciparum-K13 mutations in India. J Parasit Dis 46, 296–303 (2022). https://doi.org/10.1007/s12639-021-01425-7
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DOI: https://doi.org/10.1007/s12639-021-01425-7