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- Al-Saai, Salma, et al.
(författare)
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Distinct haplotypes of dhfr and dhps among Plasmodium falciparum isolates in an area of high level of sulfadoxine-pyrimethamine (SP) resistance in eastern Sudan
- 2009
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Ingår i: Infection, Genetics and Evolution. - : Elsevier BV. - 1567-1348 .- 1567-7257. ; 9:5, s. 778-783
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Tidskriftsartikel (refereegranskat)abstract
- Typing of polymorphic microsatellites that are linked to drug resistance genes has shed light on the origin and pattern of spread of some anti-malarial drugs. Recent surveys revealed spread of a high-level pyrimethemine resistant lineage of Plasmodium falciparum, of Asian origin, across Africa. Here, we examined mutations in dihydrofolate reductase, dhfr [chromsosome 4], the dihydropteroate synthase, dhps [chromosome 8] associated with resistance to sulfadoxine-pyrimethamine (SP), and neighboring microsatellites among P. falciparum isolates in Asar village, eastern Sudan. This area lies at the fringes of malaria endemicity, where the remote P. falciparum parasites have some distinct genetic characteristics. Overall, 89% (84/94) of the examined isolates carried double mutations at dhfr (N51I and S108N), but the 59R and I164L mutations were not seen. Similarly, the majority, 43% (35/81) of the isolates carried double mutations at dhps (437G, 540E). Analysis of neighboring microsatellites revealed one major dhfr haplotype with mutations (51I, 108N) and one dhps haplotype with mutations (436S, 437G, 540E). These haplotypes differ from the major ones thought to drive resistance to SP across Africa. The resistant haplotypes of dhfr and dhps, in Asar, share some microsatellites with the wild genotypes suggesting that they were generated locally. Among isolates successfully examined, 40% shared identical haplotypes of the 2 loci, comprising a dominant resistant lineage. Undoubtedly, this lineage plays an important role in clinical failure to SP in this area.
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| 4. |
- Kheir, Amany, et al.
(författare)
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Fitness cost of drug resistance in malaria parasites
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Version:1.0 StartHTML:0000000186 EndHTML:0000006024 StartFragment:0000002654 EndFragment:0000005988 SourceURL:file://localhost/Users/gotes/Desktop/Amany%20disp/Paper%20IV-2011.doc @font-face { font-family: "Times New Roman"; }@font-face { font-family: "Times New Roman Italic"; }p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 0cm 0cm 0.0001pt; font-size: 12pt; font-family: "Times New Roman"; }table.MsoNormalTable { font-size: 10pt; font-family: "Times New Roman"; }div.Section1 { page: Section1; } Many field surveys have demonstrated a decline in the prevalence of drug resistant parasites following withdrawal of drugs, implying fitness cost of mutations causing resistance. However, for clear ethical reason, within-host dynamics of drug-resistant mutants and sensitive forms in the absence of the drug has not been investigated in nature. Here we monitored longevity of drug resistant Plasmodium falciparum parasites in a small village in eastern Sudan with a long dry period followed by a brief annual rains and appearance of Anopheles mosquitoes. This allows tracing the fate of drug resistant P. falciparum clones, in the absence of selective drug pressure, over a period of 7 to 8 months, in the dry season. Two cohorts were examined, (a) 83 patients enrolled in October 1993 and monitored to December 1994, and (b) 121 patients recruited in October 2001 and followed-up to December 2002. Patients in both cohorts were treated, on diagnosis, with chloroquine (25mg/kg) and then followed monthly, in each visit a blood sample was collected and a patient was treated only if fever and visible parasitaemia were detected. We used PCR and RT-PCR to detect parasites and gametocytes that persisted at sub-patent levels in the dry season, respectively. In addition, we examined alleles of genes controlling the response of P. falciparum to chloroquine; the chloroquine resistance transporter (Pfcrt76T) and the multi-drug resistance protein (Pfmdr186Y). A large proportion of both cohorts maintained gametocytes producing sub-patent asymptomatic P. falciparum infections throughout the dry season. Mutant alleles of Pfcrt76T reached fixation following CQ treatment and remained high in the transmission season, a reflection of selection. However, at the start of the dry season, wild type alleles of both genes (Pfcrt76K and Pfmdr186N) started to emerge and increased significantly in frequency as the season progressed. Some members of both cohorts, encountered malaria episode in the ensuing transmission season, all of them were found to harbour parasite with wild type alleles for both genes. The above data has clearly shown selective disadvantage of CQ resistant genotypes (Pfcrt76T, Pfmdr186Y) in the absence of the drug. The data were discussed in the context of fitness of drug resistant parasite and its epidemiological impact.
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