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Fitness cost of drug resistance in malaria parasites
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Göte Swedberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Göte Swedberg)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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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.

Keyword [en]
Plasmodium falciparum, fitness cost, chloroquine resistance, pfcrt, pfmdr1
National Category
Infectious Medicine
Research subject
Biology with specialization in Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-150253OAI: oai:DiVA.org:uu-150253DiVA: diva2:406863
Available from: 2011-03-29 Created: 2011-03-28 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Factors Influencing Evolution to Antimalarial Drug Resistance in Plasmodium falciparum in Sudan and The Gambia
Open this publication in new window or tab >>Factors Influencing Evolution to Antimalarial Drug Resistance in Plasmodium falciparum in Sudan and The Gambia
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug resistance is a major obstacle to management and control of malaria and currently progressing at a rapid rate across Africa. This thesis has examined factors influencing evolution of resistant P. falciparum at two sites in Africa, including parasite migration, cross mating and fitness cost of resistance. In Asar village, eastern Sudan, the frequencies of drug sensitive and resistant parasites were monitored throughout the dry season in the absence of anti-malarial drug usage to examine whether persistence of resistant parasites is reduced in the absence of drug pressure. Two cohorts of P. falciparum infected patients were treated with chloroquine in the transmission season (Oct-Dec), and followed monthly in the dry season into the next transmission season. A large proportion of the cohort maintained sub-patent asymptomatic P. falciparum infections throughout the entire study period. Alleles of the chloroquine resistance transporter (Pfcrt) and multi-drug resistance protein (Pfmdr1) were examined. Mutant alleles of Pfcrt reached fixation following CQ treatment and remained high in the transmission season. However, at the start of the dry season, wild type alleles of both genes started to emerge and increased significantly in frequency as the season progressed. The mutant Pfcrt haplotype was invariably CVIET, indicating migration of CQ resistant parasites into an area; otherwise the CVMNK haplotype is normal. In addition, microsatellite haplotypes of dihydrofolate reductase (dhfr) gene and dihydropteroate synthase (dhps) genes, which control the parasite response to pyrimethamine and sulfadoxine respectively, were characterized. One major dhfr haplotype with double dhfr mutations and two major mutant dhps haplotypes were seen in eastern Sudan. These haplotypes are distinct from those prevailing in other African countries, suggesting the likely local origin of dhfr and dhps haplotypes conferring drug resistance.

Transmission capacities of different P. falciparum clones within a single infection in The Gambia have a high ability to produce gametocytes and infect Anopheles mosquitoes even when they exist at levels not detectable by microscopy and PCR. These findings emphasize the crucial role of gametocyte complexity and infectivity in generating the remarkable diversity of P. falciparum genotypes seen in infected people. Parasites with different resistant dihydrofolate reductase (dhfr) haplotypes have the ability to infect Anopheles mosquitoes following drug treatment, and cross-mating between parasites with different dhfr haplotypes was detected. Our results showed that the major dhfr haplotype in the Gambia is similar to the common one seen in other African countries, suggesting that parasite migration plays a major role in spread of resistance. Indeed, the dominant resistant haplotype seen in infected patients was readily transmitted to infect mosquitoes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 661
Keyword
cross-mating, fitness, microsatellite haplotypes, mosquito infectivity
National Category
Infectious Medicine
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-150254 (URN)978-91-554-8044-8 (ISBN)
Public defence
2011-05-12, C10:301, Biomedical Center (BMC), Husaratan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-04-20 Created: 2011-03-28 Last updated: 2011-05-05Bibliographically approved

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