Botswana Ministry of Health, Department of Public Health, National Malaria Programme, 2015. Revised Guidelines for the Diagnosis and Treatment of Malaria in Botswana. Gaborone, Botswana: Botswana Ministry of Health.
Howes RE et al. 2015. Plasmodium vivax transmission in Africa. PLoS Negl Trop Dis 9: e0004222.
Motshoge T et al. 2016. Molecular evidence of high rates of asymptomatic P. vivax infection and very low P. falciparum malaria in Botswana. BMC Infect Dis 16: 520.
Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2: 209–218.
Miotto O et al. 2015. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet 47: 226–234.
Wurtz N et al. 2014. Role of Pfmdr1 in in vitro Plasmodium falciparum susceptibility to chloroquine, quinine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin. Antimicrob Agents Chemother 58: 7032–7040.
David-Bosne S, Clausen MV, Poulsen H, Møller JV, Nissen P, le Maire M, 2016. Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes. Nat Struct Mol Biol 23: 1–2.
Tanabe K, Mackay M, Goman M, Scaife JG, 1987. Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum. J Mol Biol 195: 273–287.
Fidock DA et al. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6: 861–871.
Djimdé A et al. 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257–263.
Duah NO, Wilson MD, Ghansah A, Abuaku B, Edoh D, Quashie NB, Koram KA, 2007. Mutations in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance genes, and treatment outcomes in Ghanaian children with uncomplicated malaria. J Trop Pediatr 53: 27–31.
Dahlström S et al. 2014. Plasmodium falciparum polymorphisms associated with ex vivo drug susceptibility and clinical effectiveness of artemisinin-based combination therapies in Benin. Antimicrob Agents Chemother 58: 1–10.
Price RN et al. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364: 438–447.
Ferreira ID, Martinelli A, Rodrigues LA, do Carmo EL, do Rosário VE, Póvoa MM, Cravo P, 2008. Plasmodium falciparum from Pará state (Brazil) shows satisfactory in vitro response to artemisinin derivatives and absence of the S769N mutation in the SERCA-type PfATPase6. Trop Med Int Health 13: 199–207.
Menegon M, Sannella AR, Majori G, Severini C, 2008. Detection of novel point mutations in the Plasmodium falciparum ATPase6 candidate gene for resistance to artemisinins. Parasitol Int 57: 233–235.
Taylor SM et al. 2015. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis 211: 680–688.
Mita T, Tanabe K, 2012. Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance. Jpn J Infect Dis 65: 465–475.
Bustos MD, Wongsrichanalai C, Delacollette C, Burkholder B, 2013. Monitoring antimalarial drug efficacy in the Greater Mekong Subregion: an overview of in vivo results from 2008 to 2010. Southeast Asian J Trop Med Public Health 44: 201–230.
Djimde AA et al. 2003. Clearance of drug-resistant parasites as a model for protective immunity in Plasmodium falciparum malaria. Am J Trop Med Hyg 69: 558–563.
González R, AtaÃde R, Naniche D, Menéndez C, Mayor A, 2012. HIV and malaria interactions: where do we stand? Expert Rev Anti Infect Ther 10: 153–165.
Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, Djimdé AA, Kouriba B, Taylor TE, Plowe CV, 2003. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187: 1870–1875.
Huang B et al. 2016. Prevalence of crt and mdr-1 mutations in Plasmodium falciparum isolates from Grande Comore island after withdrawal of chloroquine. Malar J 15: 414.
Conrad MD et al. 2014. Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children. J Infect Dis 210: 344–353.
Tumwebaze P et al. 2015. Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from Ugandan children. Antimicrob Agents Chemother 59: 3018–3030.
Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA, 2006. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis 194: 528–535.
Uhlemann AC, Ramharter M, Lell B, Kremsner PG, Krishna S, 2005. Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis 192: 1830–1835.
Witkowski B, Nicolau ML, Soh PN, Iriart X, Menard S, Alvarez M, Marchou B, Magnaval JF, Benoit-Vical F, Berry A, 2010. Plasmodium falciparum isolates with increased pfmdr1 copy number circulate in west Africa. Antimicrob Agents Chemother 54: 3049–3051.
Agyeman-Budu A, Brown C, Adjei G, Adams M, Dosoo D, Dery D, Wilson M, Asante KP, Greenwood B, Owusu-Agyei S, 2013. Trends in multiplicity of Plasmodium falciparum infections among asymptomatic residents in the middle belt of Ghana. Malar J 12: 22.
Congpuong K, Sukaram R, Prompan Y, Dornae A, 2014. Genetic diversity of the msp-1, msp-2, and glurp genes of Plasmodium falciparum isolates along the Thai-Myanmar borders. Asian Pac J Trop Biomed 4: 598–602.
Simon C, Moakofhi K, Mosweunyane T, Jibril HB, Nkomo B, Motlaleng M, Ntebela DS, Chanda E, Haque U, 2013. Malaria control in Botswana, 2008–2012: the path towards elimination. Malar J 12: 458.
Chihanga S, Haque U, Chanda E, Mosweunyane T, Moakofhi K, Jibril HB, Motlaleng M, Zhang W, Glass GE, 2016. Malaria elimination in Botswana, 2012–2014: achievements and challenges. Parasit Vectors 9: 99.
Karl S, White MT, Milne GJ, Gurarie D, Hay SI, Barry AE, Felger I, Mueller I, 2016. Spatial effects on the multiplicity of Plasmodium falciparum infections. PLoS One 11: e0164054.
Ntoumi F, Contamin H, Rogier C, Bonnefoy S, Trape JF, Mercereau-Puijalon O, 1995 .Age-dependent carriage of multiple Plasmodium falciparum merozoite surface antigen-2 alleles in asymptomatic malaria infections. Am J Trop Med Hyg 52: 81–88.
Vafa M, Troye-Blomberg M, Anchang J, Garcia A, Migot-Nabias F, 2008. Multiplicity of Plasmodium falciparum infection in asymptomatic children in Senegal: relation to transmission, age and erythrocyte variants. Malar J 7: 17.
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Drug-resistant Plasmodium falciparum is a major threat to global malaria control and elimination efforts. In Botswana, a southern African country approaching malaria elimination, P. falciparum molecular data are not available. Parasites were assessed through pollymerase chain reaction (PCR) for confirmation of positive rapid diagnostic tests, multiplicity of infection (MOI), and drug resistance markers among isolates from clinical uncomplicated malaria cases collected at health facilities. Of 211 dried blood spot samples selected for the study, 186 (88.2%) were PCR positive for P. falciparum. The mean MOI based on MSP1 genotyping was 2.3 and was not associated with age. A high prevalence of wild-type parasites for pfcrt and pfmdr1 was found, with a haplotype frequency (K76/N86) of 88.8% and 17.7% of the isolates having two copies of the pfmdr1 gene. For pfATPase6, all the parasites carried the wild-type S769 allele. Sequencing showed no evidence of non-synonymous mutations associated with reduced artemisinin derivative sensitivity in the P. falciparum k13 gene. In conclusion, we found that P. falciparum parasites in Botswana were mostly wild type for the drug resistance markers evaluated. Yet, there was a high rate of a molecular marker associated to reduced sensitivity to lumefantrine. Our results indicate the need for systematic drug efficacy surveillance to complement malaria elimination efforts.
Financial support: This study was supported by the Botswana Ministry of Health and Wellness; the University of Botswana (Faculty of Health Sciences); the Penn Center for AIDS Research (CFAR), a National Institutes of Health–funded program [grant #P30 AI 045008 to G. M. P and C. W. M.]; and by the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [grant #DEL-15-006 to L. T.]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [grant #107752/Z/15/Z] and the U.K. government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the U.K. government.
Authors’ addresses: Leabaneng Tawe, Department of Medical Laboratory Sciences, University of Botswana, Gaborone, Botswana, Department of Medicine, Botswana-University of Pennsylvania Partnership, Gaborone, Botswana, and Laboratory, Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) at Botswana-Harvard Partnership, Gaborone, Botswana, E-mail: tleabaneng@yahoo.com. Michela Menegon, Mariangela L'Episcopia, and Carlo Severini, Department of Infectious, Parasitic and Immuno-mediated Diseases (MIPI), Istituto Superiore di Sanita, Rome, Italy, E-mails: michela.menegon@iss.it, mlepiscopia@gmail.com, and carlo.severini@iss.it. Pleasure Ramatlho and Thato Motshoge, Department of Biological Sciences, University of Botswana, Gaborone, Botswana, E-mails: pleasureram@gmail.com and motshogethato@yahoo.com. Charles W. Muthoga, Department of Medicine, Botswana-University of Pennsylvania Partnership, Gaborone, Botswana, E-mail: chmuthoga@gmail.com. Naledi Mutukwa, Department of Pathology, University of Botswana, Gaborone, Botswana, E-mail: Mutukwanb@mopipi.ub.bw. Moses Vurayai, National Health Laboratory, Department of Microbiology, Gaborone, Botswana, E-mail: mvurayai@gmail.com. Wame Bothudile and Ishmael Kasvosve, Department of Medical Laboratories Science, University of Botswana, Gaborone, Botswana, E-mails: wbothudile@yahoo.com and ishmael.kasvosve@mopipi.ub.bw. Tjantilili Mosweunyane, Ministry of Health and Wellness, National Malaria Program, Gaborone, Botswana, E-mail: tmosweunyane@gov.bw. Giacomo M. Paganotti, Department of Medicine, Botswana-University of Pennsylvania Partnership, Gaborone, Botswana, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, and Department of Biomedical Sciences, University of Botswana, Gaborone, Botswana, E-mail: paganottig@bup.org.bw.
Botswana Ministry of Health, Department of Public Health, National Malaria Programme, 2015. Revised Guidelines for the Diagnosis and Treatment of Malaria in Botswana. Gaborone, Botswana: Botswana Ministry of Health.
Howes RE et al. 2015. Plasmodium vivax transmission in Africa. PLoS Negl Trop Dis 9: e0004222.
Motshoge T et al. 2016. Molecular evidence of high rates of asymptomatic P. vivax infection and very low P. falciparum malaria in Botswana. BMC Infect Dis 16: 520.
Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR, 2002. Epidemiology of drug-resistant malaria. Lancet Infect Dis 2: 209–218.
Miotto O et al. 2015. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet 47: 226–234.
Wurtz N et al. 2014. Role of Pfmdr1 in in vitro Plasmodium falciparum susceptibility to chloroquine, quinine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin. Antimicrob Agents Chemother 58: 7032–7040.
David-Bosne S, Clausen MV, Poulsen H, Møller JV, Nissen P, le Maire M, 2016. Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes. Nat Struct Mol Biol 23: 1–2.
Tanabe K, Mackay M, Goman M, Scaife JG, 1987. Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum. J Mol Biol 195: 273–287.
Fidock DA et al. 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6: 861–871.
Djimdé A et al. 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344: 257–263.
Duah NO, Wilson MD, Ghansah A, Abuaku B, Edoh D, Quashie NB, Koram KA, 2007. Mutations in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance genes, and treatment outcomes in Ghanaian children with uncomplicated malaria. J Trop Pediatr 53: 27–31.
Dahlström S et al. 2014. Plasmodium falciparum polymorphisms associated with ex vivo drug susceptibility and clinical effectiveness of artemisinin-based combination therapies in Benin. Antimicrob Agents Chemother 58: 1–10.
Price RN et al. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364: 438–447.
Ferreira ID, Martinelli A, Rodrigues LA, do Carmo EL, do Rosário VE, Póvoa MM, Cravo P, 2008. Plasmodium falciparum from Pará state (Brazil) shows satisfactory in vitro response to artemisinin derivatives and absence of the S769N mutation in the SERCA-type PfATPase6. Trop Med Int Health 13: 199–207.
Menegon M, Sannella AR, Majori G, Severini C, 2008. Detection of novel point mutations in the Plasmodium falciparum ATPase6 candidate gene for resistance to artemisinins. Parasitol Int 57: 233–235.
Taylor SM et al. 2015. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis 211: 680–688.
Mita T, Tanabe K, 2012. Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance. Jpn J Infect Dis 65: 465–475.
Bustos MD, Wongsrichanalai C, Delacollette C, Burkholder B, 2013. Monitoring antimalarial drug efficacy in the Greater Mekong Subregion: an overview of in vivo results from 2008 to 2010. Southeast Asian J Trop Med Public Health 44: 201–230.
Djimde AA et al. 2003. Clearance of drug-resistant parasites as a model for protective immunity in Plasmodium falciparum malaria. Am J Trop Med Hyg 69: 558–563.
González R, AtaÃde R, Naniche D, Menéndez C, Mayor A, 2012. HIV and malaria interactions: where do we stand? Expert Rev Anti Infect Ther 10: 153–165.
Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, Djimdé AA, Kouriba B, Taylor TE, Plowe CV, 2003. Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187: 1870–1875.
Huang B et al. 2016. Prevalence of crt and mdr-1 mutations in Plasmodium falciparum isolates from Grande Comore island after withdrawal of chloroquine. Malar J 15: 414.
Conrad MD et al. 2014. Comparative impacts over 5 years of artemisinin-based combination therapies on Plasmodium falciparum polymorphisms that modulate drug sensitivity in Ugandan children. J Infect Dis 210: 344–353.
Tumwebaze P et al. 2015. Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from Ugandan children. Antimicrob Agents Chemother 59: 3018–3030.
Sidhu AB, Uhlemann AC, Valderramos SG, Valderramos JC, Krishna S, Fidock DA, 2006. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J Infect Dis 194: 528–535.
Uhlemann AC, Ramharter M, Lell B, Kremsner PG, Krishna S, 2005. Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis 192: 1830–1835.
Witkowski B, Nicolau ML, Soh PN, Iriart X, Menard S, Alvarez M, Marchou B, Magnaval JF, Benoit-Vical F, Berry A, 2010. Plasmodium falciparum isolates with increased pfmdr1 copy number circulate in west Africa. Antimicrob Agents Chemother 54: 3049–3051.
Agyeman-Budu A, Brown C, Adjei G, Adams M, Dosoo D, Dery D, Wilson M, Asante KP, Greenwood B, Owusu-Agyei S, 2013. Trends in multiplicity of Plasmodium falciparum infections among asymptomatic residents in the middle belt of Ghana. Malar J 12: 22.
Congpuong K, Sukaram R, Prompan Y, Dornae A, 2014. Genetic diversity of the msp-1, msp-2, and glurp genes of Plasmodium falciparum isolates along the Thai-Myanmar borders. Asian Pac J Trop Biomed 4: 598–602.
Simon C, Moakofhi K, Mosweunyane T, Jibril HB, Nkomo B, Motlaleng M, Ntebela DS, Chanda E, Haque U, 2013. Malaria control in Botswana, 2008–2012: the path towards elimination. Malar J 12: 458.
Chihanga S, Haque U, Chanda E, Mosweunyane T, Moakofhi K, Jibril HB, Motlaleng M, Zhang W, Glass GE, 2016. Malaria elimination in Botswana, 2012–2014: achievements and challenges. Parasit Vectors 9: 99.
Karl S, White MT, Milne GJ, Gurarie D, Hay SI, Barry AE, Felger I, Mueller I, 2016. Spatial effects on the multiplicity of Plasmodium falciparum infections. PLoS One 11: e0164054.
Ntoumi F, Contamin H, Rogier C, Bonnefoy S, Trape JF, Mercereau-Puijalon O, 1995 .Age-dependent carriage of multiple Plasmodium falciparum merozoite surface antigen-2 alleles in asymptomatic malaria infections. Am J Trop Med Hyg 52: 81–88.
Vafa M, Troye-Blomberg M, Anchang J, Garcia A, Migot-Nabias F, 2008. Multiplicity of Plasmodium falciparum infection in asymptomatic children in Senegal: relation to transmission, age and erythrocyte variants. Malar J 7: 17.
Past two years | Past Year | Past 30 Days | |
---|---|---|---|
Abstract Views | 235 | 195 | 9 |
Full Text Views | 492 | 11 | 0 |
PDF Downloads | 187 | 8 | 0 |