title: Different origin and dispersal of sulfadoxine-resistant Plasmodium falciparum haplotypes between Eastern Africa and Democratic Republic of Congo.
abstract: Sulfadoxine/pyrimethamine (SP) is still used for malaria control in sub-Saharan Africa; however, widespread resistance is a major concern. This study aimed to determine the dispersal and origin of sulfadoxine resistance lineages in the Democratic Republic of the Congo compared with East African Plasmodium falciparum dihydropteroate synthetase (Pfdhps) haplotypes. The analysis involved 264 isolates collected from patients with uncomplicated malaria from Tanzania, Uganda and DR Congo. Isolates were genotyped for Pfdhps mutations at codons 436, 437, 540, 581 and 613. Three microsatellite loci (0.8, 4.3 and 7.7 kb) flanking the Pfdhps gene were assayed. Evolutionary analysis revealed a shared origin of Pfdhps haplotypes in East Africa, with a distinct population clustering in DR Congo. Furthermore, in Tanzania there was an independent distinct origin of Pfdhps SGEGA resistant haplotype. In Uganda and Tanzania, gene flow patterns contribute to the dispersal and shared origin of parasites carrying double- and triple-mutant Pfdhps haplotypes associated with poor outcomes of intermittent preventive treatment during pregnancy using SP (IPTp-SP). However, the origins of the Pfdhps haplotypes in DR Congo and Eastern Africa sites are different. The genetic structure demonstrated a divergent and distinct population cluster predominated by single-mutant Pfdhps haplotypes at the DR Congo site. This reflects the limited dispersal of double- and triple-mutant Pfdhps haplotypes in DR Congo. This study highlights the current genetic structure and dispersal of high-grade Pfdhps resistant haplotypes, which is important to guide implementation of SP in malaria chemoprevention strategies in the region.
authors.affiliation: National Institute for Medical Research, Tanga Research Centre, P.O. Box 5004, Tanga, United Republic of Tanzania; Global Health Institute, University of Antwerp, Antwerp, Belgium. Electronic address: vitobaraka@gmail.com.
authors.forename: Vito
authors.initials: V
authors.lastname: Baraka
authors.affiliation: Global Health Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Christopher
authors.initials: C
authors.lastname: Delgado-Ratto
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, National University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Nag
authors.affiliation: National Institute for Medical Research, Tanga Research Centre, P.O. Box 5004, Tanga, United Republic of Tanzania.
authors.forename: Deus S
authors.initials: DS
authors.lastname: Ishengoma
authors.affiliation: National Institute for Medical Research, Tanga Research Centre, P.O. Box 5004, Tanga, United Republic of Tanzania.
authors.forename: Rashid A
authors.initials: RA
authors.lastname: Madebe
authors.affiliation: Global Health Institute, University of Antwerp, Antwerp, Belgium; Département de Médecine Tropicale, Faculté de Médecine, Université de Kinshasa, B.P. 747 Kin XI, Kinshasa, The Democratic Republic of the Congo.
authors.forename: Hypolite Muhindo
authors.initials: HM
authors.lastname: Mavoko
authors.affiliation: Global Health Institute, University of Antwerp, Antwerp, Belgium; Epicentre Mbarara Research Base, P.O. Box 930, Mbarara, Uganda.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Nabasumba
authors.affiliation: Département de Médecine Tropicale, Faculté de Médecine, Université de Kinshasa, B.P. 747 Kin XI, Kinshasa, The Democratic Republic of the Congo.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lutumba
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, National University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Alifrangis
authors.affiliation: Global Health Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Van Geertruyden
mesh_terms: D000351:Africa, Eastern / Q000453:epidemiology; D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D015023:Democratic Republic of the Congo / Q000453:epidemiology; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004351:Drug Resistance; D005260:Female; D014644:Genetic Variation; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000469:parasitology; D008297:Male; D018895:Microsatellite Repeats; D010963:Plasmodium falciparum / Q000145:classification / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D013413:Sulfadoxine / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D013413:Sulfadoxine; D004094:Dihydropteroate Synthase
keywords: Drug resistance; Microsatellites; Molecular evolution; Pfdhps; Plasmodium falciparum; Sulfadoxine