Source of drug resistant Plasmodium falciparum in a potential malaria elimination site in Saudi Arabia

• Published in: Infection, genetics and evolution genetics and evolution, 2012-08, Vol.12 (6), p.1253-1259
• Main Authors: Al-Farsi, Hissa M., Al-Hashami, Zainab S., Bin Dajem, Saad M., Al-Sheikh, Adel Ali H., Al-Qahtani, Ahmed, Beja-Pereira, Albano, Idris, Mohamed A., Babiker, Hamza A.
• Format: Article
• Language: English
• Subjects: alleles; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; data collection; dihydrofolate reductase; Dihydropteroate Synthase - genetics; DNA, Protozoan - analysis; DNA, Protozoan - genetics; Drug Combinations; Drug Resistance; drugs; Epidemiology. Vaccinations; Evolutionary origin; General aspects; Haplotypes; heterozygosity; Human protozoal diseases; Humans; Infectious diseases; loci; Malaria; Malaria, Falciparum - parasitology; Malaria, Falciparum - prevention & control; Malaria, Falciparum - transmission; Medical sciences; Microsatellite Repeats; Models, Genetic; monitoring; mutants; Mutation; parasites; Parasitic diseases; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Protozoal diseases; Pyrimethamine - pharmacology; Pyrimethamine–sulfadoxine resistance; Saudi Arabia; Sulfadoxine - pharmacology; Tetrahydrofolate Dehydrogenase - genetics; therapeutics
• ISSN: 1567-1348; 1567-7257
• DOI: 10.1016/j.meegid.2012.03.011

► Eight out of nine resistant dhfr haplotypes seen in Saudi Arabia carried double mutations (51I, 108N). ► The major double mutant dhfr haplotype has a close evolutionary relationship to east Africa. ► Parasite migration is a plausible source of this lineage. ► A high level of parasite diversity was seen in Jazan, despite the low transmission levels and adequate access to therapy. ► SP pressure is not enough to offset the recurrent arrival (i.e., gene-flow) of mutant haplotypes from outside. A major challenge to the success of malaria control program in Saudi Arabia is the high influx of expatriates and holy visitors from malaria endemic countries. In the present study we examined whether drug resistant parasite genotypes reported in Jazan region, southwest of Saudi Arabia are imported or developed locally. We examined 178 Plasmodium falciparum isolates for alleles of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), associated with Sulfadoxine-Pyrimethamine (SP) resistance, and three microsatellites flanking each gene. In addition, we examined a neutral polymorphic gene (Pfg377). We compared the dhfr and dhps haplotypes in Jazan, using network analysis, to an existing similar data set of 94 P. falciparum isolates from eastern Sudan. In Jazan, double mutant dhfr allele (51I, 108N) occurred with a prevalence of 33%. The vast majority (99%) of dhps were wild-type alleles. The mean expected heterozygosity (He) of microsatellites around mutant dhfr alleles (He=0.312; n=60) was lower (P⩽0.05) than that around the wild-type allele (He=0.834; n=116). Also, the mutant dhfr isolates showed high He for dhps (He=0.80) and the non-drug resistance locus Pfg377 (He=0.63) indicative of selection for mutant dhfr only. The predominant double mutant dhfr haplotype in Jazan (73%), was prevalent among P. falciparum in east Africa. Network analysis suggests the mutant haplotype of dhfr gene was possibly introduced into Jazan from East Africa. The absence of mutations in dhps as well as triple mutant dhfr haplotype associated with SP failure support the current use of SP as a partner with artesunate as a first line therapy in Saudi Arabia. However, the close relationship between the major mutant dhfr haplotype in Sudan and Saudi Arabia, favour the hypothesis of recent migration as a source of the major resistant dhfr lineage. Thus, regular monitoring of the dhfr and dhps haplotypes is of high priority to guard possible importation of high level SP resistant li