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

Abstract

BackgroundTo 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.MethodsBlood 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 T1069ACT→ACG 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).ConclusionsChloroquine treatment possibly resulted in the development of pfcrt 72–76 CVIET. Selection of pfmdr1 T1069ACG 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1747-6) contains supplementary material, which is available to authorized users.

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

“…Genetic polymorphisms associated with parasite resistance to chloroquine and pyrimethamine were detected in rural Liberia as early as 1978 [ 52 ]. Three decades later, resistance to chloroquine and SP continued to rise [ 53 ].…”

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

“…Indeed, the QN sensitivities of isolates with different numbers of DNNND and NHNDHNNDDD repeats were compared [34]. Sequence polymorphisms of ms4760 in pfnhe1 have been analyzed, especially in Block II and V [41]. Studies of the association of polymorphisms in Block II and V with in vitro susceptibility to QN have shown conflicting results.…”

“…Studies of the association of polymorphisms in Block II and V with in vitro susceptibility to QN have shown conflicting results. A study showed that more than one DNNND repeat in Block II and one NHNDNHNNDDD repeat in Block V in ms4760 were associated with reduced QN sensitivity in vivo [41]. The same study illustrated that isolates from Vietnam and the China-Myanmar border containing two or more DNNND repeats showed a much lower susceptibility to QN than those containing 0 or 1 repeats, and an increased number of NHNDNHNNDDD repeats was associated with high QN susceptibility in vitro [33, 42].…”

Plasmodium falciparum Multidrug Resistance Proteins (pfMRPs)

“…The global distribution of SNPs is variable, with some positions being widely distributed, like the frequently linked Y191H/A437S ( Mu et al, 2003 ; Ursing et al, 2006 ; Pirahmadi et al, 2013 ), as well as I876V ( Dahlstrom et al, 2009 ; Gupta et al, 2014 ; Zhao et al, 2019 ; Al-Ruhmi et al, 2020 ), which seems to have been circulating at least since pre-chloroquine times ( de Dios et al, 2019 ). Others are clustered in some regions, like the 1466 position, frequent in East Africa ( Dahlstrom et al, 2009 ; 2009a ), but rare in the Western coast ( Otienoburu et al, 2016 ; Jovel et al, 2017 ), and found absent in studies in Asia ( Veiga et al, 2011 ; Gupta et al, 2014 ; Phompradit et al, 2014 ) as well as in the Americas ( Dahlstrom et al, 2009 ). Pfmrp1 gene copy number variation has been observed in vitro ( Bopp et al, 2013 ) and is also likely to exist in the field, as recently suggested through deep analysis of next generation sequencing archive data from West African parasites ( Yini et al, 2018 ).…”