The implication of dihydrofolate reductase and dihydropteroate synthetase gene mutations in modification of Plasmodium falciparum characteristics.
BACKGROUND
The Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) are enzymes of central importance in parasite metabolism. The dhfr and dhps gene mutations are known to be associated with sulphadoxine/pyrimethamine (SP) resistance.


OBJECTIVE
To investigate the effects of dhfr/dhps mutations on parasite characteristics other than SP resistance.


METHODS
Parasite infections obtained from 153 Sudanese patients with uncomplicated falciparum malaria treated with SP or SP + chloroquine, were successfully genotyped at nine codons in the dhfr/dhps genes by PCR-ELISA.


CONCLUSIONS
Mutations were detected in dhfr at N51I, S108N and C59R, and in at dhps at A/S436F, A437G, K540E and A581G, the maximum number of mutations per infection were five. Based on number of mutant codons per infection (multiplicity of mutation, MOM), the infections were organized into six grades: wild-types (grade 0; frequency, 0.03) and infections with MOM grades of 1 to 5, with the following cumulative frequency; 0.97, 0.931, 0.866, 0.719, 0.121, respectively. There was no significant association between the MOM and SP response. Importantly, immunity, using age as a surrogate marker, contributed significantly to the clearance of parasites with multiple dhfr/dhps mutations. However, these mutations have a survival advantage as they were associated with increased gametocytogenesis. The above implications of dhfr/dhps mutations were associated with MOM 2 to 5, regardless of the gene/codon locus.
A-Elbasit
Ishraga E
IE
Malaria Research Centre (MalRC), Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. ishraga20@yahoo.co.uk <ishraga20@yahoo.co.uk>
Alifrangis
Michael
M
Khalil
Insaf F
IF
Bygbjerg
Ib C
IC
Masuadi
Emad M
EM
Elbashir
Mustafa I
MI
Giha
Hayder A
HA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D002738:Chloroquine / Q000627:therapeutic use; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005787:Gene Frequency; D017125:Genes, Protozoan; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D017354:Point Mutation; D015800:Protozoan Proteins / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
D000962:Antimalarials; D004338:Drug Combinations; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D002738:Chloroquine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine