Molecular determinants of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum in Nigeria and the regional emergence of dhps 431V.
There are few published reports of mutations in dihydropteroate synthetase (dhps) and dihydrofolate reductase (dhfr) genes in P. falciparum populations in Nigeria, but one previous study has recorded a novel dhps mutation at codon 431 among infections imported to the United Kingdom from Nigeria. To assess how widespread this mutation is among parasites in different parts of the country and consequently fill the gap in sulfadoxine-pyrimethamine (SP) resistance data in Nigeria, we retrospectively analysed 1000 filter paper blood spots collected in surveys of pregnant women and children with uncomplicated falciparum malaria between 2003 and 2015 from four sites in the south and north. Genomic DNA was extracted from filter paper blood spots and placental impressions. Point mutations at codons 16, 50, 51, 59, 108, 140 and 164 of the dhfr gene and codons 431, 436, 437, 540, 581 and 613 of the dhps gene were evaluated by nested PCR amplification followed by direct sequencing. The distribution of the dhps-431V mutation was widespread throughout Nigeria with the highest prevalence in Enugu (46%). In Ibadan where we had sequential sampling, its prevalence increased from 0% to 6.5% between 2003 and 2008. Although there were various combinations of dhps mutations with 431V, the combination 431V + 436A + 437G+581G+613S was the most common. All these observations support the view that dhps-431V is on the increase. In addition, P. falciparum DHPS crystal structure modelling shows that the change from Isoleucine to Valine (dhps-431V) could alter the effects of both S436A/F and A437G, which closely follow the 2nd β-strand. Consequently, it is now a research priority to assess the implications of dhps-VAGKGS mutant haplotype on continuing use of SP in seasonal malaria chemoprevention (SMC) and intermittent preventive treatment in pregnancy (IPTp). Our data also provides surveillance data for SP resistance markers in Nigeria between 2003 and 2015.
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom. Electronic address: mary.oguike@lshtm.ac.uk.
Mary C
MC
Oguike
Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
Catherine O
CO
Falade
Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, Enugu Campus, Enugu, Nigeria.
Elvis
E
Shu
Department of Child Health, University of Benin Teaching Hospital, Benin City, Nigeria.
Izehiuwa G
IG
Enato
Department of Paediatrics, Specialist Hospital Maiduguri, Borno State, Nigeria.
Ismaila
I
Watila
Malaria Consortium, Regional Office for Africa, Kampala, Uganda.
Ebenezer S
ES
Baba
Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Jane
J
Bruce
Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Jayne
J
Webster
Malaria Consortium, London, United Kingdom.
Prudence
P
Hamade
Malaria Consortium, London, United Kingdom.
Sylvia
S
Meek
Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Daniel
D
Chandramohan
Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Colin J
CJ
Sutherland
Department of Pathogen Molecular Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
David
D
Warhurst
Department of Pathogen Molecular Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Cally
C
Roper
D000328:Adult; D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D050505:Mutant Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009549:Nigeria; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000469:parasitology; D011739:Pyrimethamine / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology*; D055815:Young Adult
D000962:Antimalarials; D016054:DNA, Protozoan; D004338:Drug Combinations; D050505:Mutant Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine
Nigeria; Sulfadoxine-pyrimethamine; dhfr; dhps; mutations