Volume 6, Issue 2, June 2020, Page: 38-43
Distribution and Contribution of K13-propeller Gene to Artemisinin Resistance in sub-Saharan Africa: A Systematic Review
Laura Nyawira Wangai, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Kenny Kimani Kamau, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Immaculate Marwa, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Elly OMunde, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Samuel Mburu, School of Health Sciences, Kirinyaga University, Kutus, Kenya
John Mwangi, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Mark Webale, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Dennis Butto, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Lucy Kamau, School of Health Sciences, Kirinyaga University, Kutus, Kenya
John Hiuhu, School of Health Sciences, Kirinyaga University, Kutus, Kenya
Received: May 26, 2020;       Accepted: Jun. 10, 2020;       Published: Jun. 20, 2020
DOI: 10.11648/j.bs.20200602.14      View  290      Downloads  85
The observed clinical failure after treatment with artemisinin combination therapy (ACT) has recently been confirmed in western Cambodia. Evidence of declining ACT efficacy has also been reported in Africa. Molecular markers for artemisinin resistance have played an essential role in monitoring the spread of the resistant phenotype and identifying the mechanisms of resistance. Several candidate genes, including the P. falciparum kelch propeller region (K13). However, in sub-Saharan Africa, despite the observed delayed clearance after treatment, the association between ART resistance and K13 gene is questionable as studies have not found significant mutations or an association with the delayed parasite clearance rate following ACT treatment. There is need for more data to clarify the significance of K13-propeller mutations as markers of artemisinin resistance in Africa. An electronic search of studies in sub-Saharan Africa from 2014 to date was done via PubMED, SCOPUS, and EMBASE databases. The search was conducted independently by two librarians. The articles were screened for selection using a priori criteria set following PRISMAP and STREGA guidelines. Data analysis was performed in R-statistics software. A total of 197 articles were identified from Pubmed=139, Research gate=40, Bibliography/other searches=18, of which 102 did not meet the selection criteria. A total of 74 independent K13 mutations were identified across malaria-affected African countries. Only 7 unconfirmed K13 mutations were associated with delayed parasite clearance half-life (t1/2>3 h). The majority, 47.5% (35/74), of the mutations were reported in single P. falciparum parasite isolate. Of the 74 K13-mutations, nearly two-thirds were reported as new alleles. Twenty-seven (27) non-synonymous mutations in the Pfkelch13 gene were identified. Although artemisinin resistance in South-East Asia seems to be a heritable genetic trait, none of the candidate genes suggested by earlier studies confer artemisinin resistance to the observed clinical failure in Africa. Mutations outside the Pfkelch13 propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions in Africa. The use of a genome-wide approach by whole genome sequencing and gene expression transcriptome studies to identify the molecular basis of artemisinin resistance is warranted to aid in identification potential markers for ACT resistance in Africa.
Malaria, Artemisinin Resistance, K13-propeller Gene Polymorphism, Sub-Saharan Africa, Plasmodium falciparum
To cite this article
Laura Nyawira Wangai, Kenny Kimani Kamau, Immaculate Marwa, Elly OMunde, Samuel Mburu, John Mwangi, Mark Webale, Dennis Butto, Lucy Kamau, John Hiuhu, Distribution and Contribution of K13-propeller Gene to Artemisinin Resistance in sub-Saharan Africa: A Systematic Review, Biomedical Sciences. Vol. 6, No. 2, 2020, pp. 38-43. doi: 10.11648/j.bs.20200602.14
Copyright © 2020 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ippolito MM, Johnson J, Mullin C, Mallow C, Morgan N, Wallender E, et al. The relative effects of artemether-lumefantrine and non-artemisinin antimalarials on gametocyte carriage and transmission of Plasmodium falciparum: a systematic review and meta-analysis. Clinical Infectious Diseases. 2017; 65 (3): 486–494.
Woodrow CJ, White NJ. The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread. FEMS microbiology reviews. 2017; 41 (1): 34–48.
Nyunt MH, Soe MT, Myint HW, Oo HW, Aye MM, Han SS, et al. Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009–2013). Malaria journal. 2017; 16 (1): 333.
Organization WH. World malaria report 2019. 2019.
Escobar C, Pateira S, Lobo E, Lobo L, Teodosio R, Dias F, et al. Polymorphisms in Plasmodium falciparum K13-propeller in Angola and Mozambique after the introduction of the ACTs. PloS one. 2015; 10 (3).
Straimer J, Gnädig NF, Stokes BH, Ehrenberger M, Crane AA, Fidock DA. Plasmodium falciparum K13 mutations differentially impact ozonide susceptibility and parasite fitness in vitro. MBio. 2017; 8 (2): e00172–17.
Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois A-C, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014; 505 (7481): 50–55.
Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. The Lancet Infectious Diseases. 2017; 17 (5): 491–497.
Visser BJ, Wieten RW, Kroon D, Nagel IM, Bélard S, van Vugt M, et al. Efficacy and safety of artemisinin combination therapy (ACT) for non-falciparum malaria: a systematic review. Malaria journal. 2014; 13 (1): 463.
Organization WH. Artemisinin and artemisinin-based combination therapy resistance: Status Report. World Health Organization; 2016.
Ikeda M, Kaneko M, Tachibana S-I, Balikagala B, Sakurai-Yatsushiro M, Yatsushiro S, et al. Artemisinin-resistant Plasmodium falciparum with high survival rates, Uganda, 2014–2016. Emerging infectious diseases. 2018; 24 (4): 718.
Kakolwa MA, Mahende MK, Ishengoma DS, Mandara CI, Ngasala B, Kamugisha E, et al. Efficacy and safety of artemisinin-based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania. Malaria journal. 2018; 17 (1): 369.
Kamau E, Campino S, Amenga-Etego L, Drury E, Ishengoma D, Johnson K, et al. K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. The Journal of infectious diseases. 2015; 211 (8): 1352–1355.
Torrentino-Madamet M, Fall B, Benoit N, Camara C, Amalvict R, Fall M, et al. Limited polymorphisms in k13 gene in Plasmodium falciparum isolates from Dakar, Senegal in 2012–2013. Malaria journal. 2014; 13 (1): 472.
Ouattara A, Kone A, Adams M, Fofana B, Maiga AW, Hampton S, et al. Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali. The American journal of tropical medicine and hygiene. 2015; 92 (6): 1202–1206.
de Laurent ZR, Chebon LJ, Ingasia LA, Akala HM, Andagalu B, Ochola-Oyier LI, et al. Polymorphisms in the K13 gene in Plasmodium falciparum from different malaria transmission areas of Kenya. The American journal of tropical medicine and hygiene. 2018; 98 (5): 1360–1366.
Gupta H, Macete E, Bulo H, Salvador C, Warsame M, Carvalho E, et al. Drug-resistant polymorphisms and copy numbers in Plasmodium falciparum, Mozambique, 2015. Emerging infectious diseases. 2018; 24 (1): 40.
Laminou IM, Lamine MM, Mahamadou B, Ascofaré OM, Dieye A. Polymorphism of pfk13-propeller in Niger: detection of novel mutations. Journal of Advances in Medicine and Medical Research. 2017; 1–5.
Musyoka KB, Kiiru JN, Aluvaala E, Omondi P, Chege WK, Judah T, et al. Prevalence of mutations in Plasmodium falciparum genes associated with resistance to different antimalarial drugs in Nyando, Kisumu County in Kenya. Infection, Genetics and Evolution. 2020; 78: 104121.
Mukherjee A, Bopp S, Magistrado P, Wong W, Daniels R, Demas A, et al. Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia. Malaria journal. 2017; 16 (1): 1–12.
Yang C, Zhang H, Zhou R, Qian D, Liu Y, Zhao Y, et al. Polymorphisms of Plasmodium falciparum k13-propeller gene among migrant workers returning to Henan Province, China from Africa. BMC infectious diseases. 2017; 17 (1): 560.
Straimer J, Gnädig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015; 347 (6220): 428–431.
Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, et al. Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. The Lancet infectious diseases. 2016; 16 (3): 357–365.
Cooper RA, Conrad MD, Watson QD, Huezo SJ, Ninsiima H, Tumwebaze P, et al. Lack of artemisinin resistance in Plasmodium falciparum in Uganda based on parasitological and molecular assays. Antimicrobial agents and chemotherapy. 2015; 59 (8): 5061–5064.
Muwanguzi J, Henriques G, Sawa P, Bousema T, Sutherland CJ, Beshir KB. Lack of K13 mutations in Plasmodium falciparum persisting after artemisinin combination therapy treatment of Kenyan children. Malaria journal. 2016; 15 (1): 36.
Witkowski B, Duru V, Khim N, Ross LS, Saintpierre B, Beghain J, et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study. The Lancet Infectious Diseases. 2017; 17 (2): 174–183.
Oyola SO, Ariani CV, Hamilton WL, Kekre M, Amenga-Etego LN, Ghansah A, et al. Whole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplification. Malaria journal. 2016; 15 (1): 597.
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