Unexpected Selections of Plasmodium Falciparum Polymorphisms in Previously Treatment-naïve Areas After Monthly Presumptive Administration of Three Different Anti-malarial Drugs in Liberia 1976-78

Overview

Journal Malar J

Publisher Biomed Central

Specialty Tropical Medicine

Date 2017 Mar 15

PMID 28288632

Citations 5

Authors

Irina T Jovel

Anders Bjorkman

Cally Roper

Andreas Martensson

Johan Ursing

Affiliations

Soon will be listed here.

Abstract

Background: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naïve Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P. falciparum resistance after 2 years of treatment are reported.

Methods: Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods.

Results: Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069 synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001).

Conclusions: Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069 and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.

Citing Articles

Multidrug Resistance Proteins (MRPs).

Gil J, Fancony C Front Pharmacol. 2021; 12:759422.

PMID: 34790129 PMC: 8591188. DOI: 10.3389/fphar.2021.759422.

Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19.

Lei Z, Wu Z, Dong S, Yang D, Zhang L, Ke Z Pharmacol Ther. 2020; 216:107672.

PMID: 32910933 PMC: 7476892. DOI: 10.1016/j.pharmthera.2020.107672.

Mosquitoes as a feasible sentinel group for anti-malarial resistance surveillance by Next Generation Sequencing of Plasmodium falciparum.

Smith-Aguasca R, Gupta H, Uberegui E, Maquina M, Saute F, Paaijmans K Malar J. 2019; 18(1):351.

PMID: 31623623 PMC: 6796398. DOI: 10.1186/s12936-019-2946-0.

Analysis of Plasmodium falciparum Na/H exchanger (pfnhe1) polymorphisms among imported African malaria parasites isolated in Wuhan, Central China.

Wu K, Yao Y, Chen F, Xu M, Lu G, Jiang T BMC Infect Dis. 2019; 19(1):354.

PMID: 31035938 PMC: 6489200. DOI: 10.1186/s12879-019-3921-7.

Prevalence of Plasmodium falciparum infection among pregnant women at first antenatal visit in post-Ebola Monrovia, Liberia.

Martinez-Perez G, Lansana D, Omeonga S, Gupta H, Breeze-Barry B, Gonzalez R Malar J. 2018; 17(1):357.

PMID: 30314489 PMC: 6186138. DOI: 10.1186/s12936-018-2506-z.

References

Ashley E, Dhorda M, Fairhurst R, Amaratunga C, Lim P, Suon S . Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014; 371(5):411-23. PMC: 4143591. DOI: 10.1056/NEJMoa1314981. View

Dondorp A, Nosten F, Yi P, Das D, Phyo A, Tarning J . Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009; 361(5):455-67. PMC: 3495232. DOI: 10.1056/NEJMoa0808859. View

Kone A, Mu J, Maiga H, Beavogui A, Yattara O, Sagara I . Quinine treatment selects the pfnhe-1 ms4760-1 polymorphism in Malian patients with Falciparum malaria. J Infect Dis. 2012; 207(3):520-7. PMC: 3537444. DOI: 10.1093/infdis/jis691. View

Bjorkman A, Brohult J, Pehrson P, Willcox M, Rombo L, Hedman P . Monthly antimalarial chemotherapy to children in a holoendemic area of Liberia. Ann Trop Med Parasitol. 1986; 80(2):155-67. DOI: 10.1080/00034983.1986.11812000. View

Noedl H, Se Y, Schaecher K, Smith B, Socheat D, Fukuda M . Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008; 359(24):2619-20. DOI: 10.1056/NEJMc0805011. View

Lewis I, Wacker M, Olszewski K, Cobbold S, Baska K, Tan A . Metabolic QTL analysis links chloroquine resistance in Plasmodium falciparum to impaired hemoglobin catabolism. PLoS Genet. 2014; 10(1):e1004085. PMC: 3879234. DOI: 10.1371/journal.pgen.1004085. View

Basco L, Eldin de Pecoulas P, Wilson C, Le Bras J, MAZABRAUD A . Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum. Mol Biochem Parasitol. 1995; 69(1):135-8. DOI: 10.1016/0166-6851(94)00207-4. View

Holmgren G, Hamrin J, Svard J, Martensson A, Gil J, Bjorkman A . Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. Infect Genet Evol. 2007; 7(5):562-9. DOI: 10.1016/j.meegid.2007.03.005. View

Bjorkman A, Brohult J, Sirleaf V, Willcox M, Bengtsson E . Plasmodium falciparum resistance to pyrimethamine and chlorproguanil -- host or parasite dependent?. Ann Trop Med Parasitol. 1980; 74(2):245-8. DOI: 10.1080/00034983.1980.11687336. View

10.

Sanchez C, Horrocks P, Lanzer M . Is the putative chloroquine resistance mediator CG2 the Na+/H+ exchanger of Plasmodium falciparum?. Cell. 1998; 92(5):601-2. DOI: 10.1016/s0092-8674(00)81127-7. View

11.

Muller I, Hyde J . Antimalarial drugs: modes of action and mechanisms of parasite resistance. Future Microbiol. 2010; 5(12):1857-73. DOI: 10.2217/fmb.10.136. View

12.

Fidock D, Nomura T, Talley A, Cooper R, Dzekunov S, Ferdig M . Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell. 2000; 6(4):861-71. PMC: 2944663. DOI: 10.1016/s1097-2765(05)00077-8. View

13.

Bjorkman A, Hedman P, Brohult J, Willcox M, Diamant I, Pehrsson P . Different malaria control activities in an area of Liberia--effects on malariometric parameters. Ann Trop Med Parasitol. 1985; 79(3):239-46. DOI: 10.1080/00034983.1985.11811914. View

14.

Pascual A, Fall B, Wurtz N, Fall M, Camara C, Nakoulima A . In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger transporter (Pfnhe-1) gene in 393 isolates from Dakar, Senegal. Malar J. 2013; 12:189. PMC: 3679854. DOI: 10.1186/1475-2875-12-189. View

15.

Malmberg M, Ferreira P, Tarning J, Ursing J, Ngasala B, Bjorkman A . Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms. J Infect Dis. 2012; 207(5):842-7. PMC: 3563306. DOI: 10.1093/infdis/jis747. View

16.

Bjorkman A, Rombo L, Willcox M, Hanson A, Bengtsson E . In vivo response of Plasmodium falciparum to different doses of chloroquine in semi-immune children in Liberia, West Africa. Ann Trop Med Parasitol. 1986; 80(1):1-6. DOI: 10.1080/00034983.1986.11811978. View

17.

Ferdig M, Cooper R, Mu J, Deng B, Joy D, Su X . Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol. 2004; 52(4):985-97. DOI: 10.1111/j.1365-2958.2004.04035.x. View

18.

Nwakanma D, Duffy C, Amambua-Ngwa A, Oriero E, Bojang K, Pinder M . Changes in malaria parasite drug resistance in an endemic population over a 25-year period with resulting genomic evidence of selection. J Infect Dis. 2013; 209(7):1126-35. PMC: 3952670. DOI: 10.1093/infdis/jit618. View

19.

Wunsch S, Sanchez C, Gekle M, Grosse-Wortmann L, Wiesner J, Lanzer M . Differential stimulation of the Na+/H+ exchanger determines chloroquine uptake in Plasmodium falciparum. J Cell Biol. 1998; 140(2):335-45. PMC: 2132566. DOI: 10.1083/jcb.140.2.335. View

20.

Amaratunga C, Sreng S, Suon S, Phelps E, Stepniewska K, Lim P . Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012; 12(11):851-8. PMC: 3786328. DOI: 10.1016/S1473-3099(12)70181-0. View