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    ABSTRACT: Evolution and spread of chloroquine resistant (CQR) malaria parasite Plasmodium falciparum have posed great threat in malaria intervention across the globe. The occurrence of K76T mutation in the P. falciparum chloroquine resistance transporter (pfcrt) gene has been widely attributed to CQR with four neighboring mutations providing compensatory fitness benefit to the parasite survival. Understanding evolutionary patterns of the pfcrt gene is of great relevance not only for devising new malaria control measures but also could serve as a model to understand evolution and spread of other human drug-resistant pathogens. Several studies, mainly based on differential patterns of diversities of the microsatellite loci placed in-and-around the pfcrt gene have indicated the role of positive natural selection under the 'hitchhiking' model of molecular evolution. However, the studies were restricted to limited number of microsatellite loci present inside the pfcrt gene. Moreover, comparatively higher level of diversities in microsatellite loci present inside the pfcrt gene than the loci flanking the pfcrt gene are hallmarks of Indian P. falciparum, presenting contrasting evolutionary models to global isolates. With a view to infer evolutionary patterns of the pfcrt gene in Indian P. falciparum, we have adopted a unique sampling scheme of two types of populations (cultured and field collected) and utilized 20 polymorphic microsatellite loci (16 located inside the pfcrt gene and four in the two flanking regions) to disentangle between genetic drift (inbred cultured isolates) and natural selection (field isolates). Data analyses employing different population genetic tests could not straightforwardly explain either the model invoking 'genetic hitchhiking' or 'genetic drift'. However, complex evolutionary models influenced by both demography and natural selection or an alternative model of natural selection (e.g. diversifying/balancing selection) might better explain the observed microsatellite variation in-and-around the pfcrt gene in Indian P. falciparum.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 10/2013; 20. DOI:10.1016/j.meegid.2013.10.010
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    ABSTRACT: New tools for malaria control, artemisinin combination therapy (ACT) and long-lasting insecticidal nets (LLINs) were recently introduced across India. We estimated the impact of universal coverage of ACT and ACT plus LLINs in a setting of hyperendemic, forest malaria transmission. We reviewed data collected through active and passive case detection in a vaccine trial cohort of 2,204 tribal people residing in Sundargarh district, Odisha between 2006 and 2011. We compared measures of transmission at the village and individual level in 2006-2009 versus 2010-2011 after ACT (in all villages) and LLINs (in three villages) were implemented. During 2006-2009 malaria incidence per village ranged from 156-512 per 1000 persons per year and slide prevalence ranged from 28-53%. Routine indoor residual spray did not prevent seasonal peaks of malaria. Post-intervention impact in 2010-2011 was dramatic with ranges of 14-71 per 1000 persons per year and 6-16% respectively. When adjusted for village, ACT alone decreased the incidence of malaria by 83% (IRR 0.17, 95%CI: 0.10, 0.27) and areas using ACT and LLINs decreased the incidence of malaria by 86% (IRR 0.14, 95%CI: 0.05, 0.38). After intervention, the age of malaria cases, their parasite density, and proportion with fever at the time of screening increased. ACT, and LLINs along with ACT, effectively reduced malaria incidence in a closely monitored population living in a forest ecotype. It is unclear whether LLINs were impactful when prompt and quality antimalarial treatment was available. In spite of universal coverage, substantial malaria burden remained.
    PLoS ONE 10/2013; 8(2):e56740. DOI:10.1371/journal.pone.0056740
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    ABSTRACT: The positive selection of a nucleotide substitution in exon 2 of Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene (mutation responsible for chloroquine resistance) causes a reduction in variation of neutral loci close to the gene. This reduction in allelic diversity around flanking regions of pfcrt gene was reported in worldwide chloroquine resistant isolates and referred as selective sweep. In Plasmodium falciparum isolates of India, the selective sweep in flanking loci of pfcrt gene is well established, however, high allelic diversity observed in intragenic microsatellites of pfcrt gene implied an ongoing genetic recombination. To understand, if molecular evolution of chloroquine-resistant P. falciparum isolates in India follow a selective sweep model, we analyzed genetic diversity at both seven intragenic and seven flanking microsatellites of pfcrt (-24kb to +106kb) gene in chloroquine sensitive and resistant parasites originating from high and low transmission areas. We observed low expected heterozygosity at all loci of resistant pfcrt-haplotypes (He= 0-0.77) compared to the wild-type (He= 0.38-0.96). Resistant SVMNT from high transmission areas showed significantly higher mean He (P=0.03, t-test) at both intragenic and pfcrt-flanking loci (-24kb to +22kb) in comparison to low transmission areas. Our observation of reduction in variation at both intragenic and flanking loci of mutant pfcrt gene confirmed the selective sweep model of natural selection in chloroquine resistant P. falciparum isolates in India.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 10/2013; 20. DOI:10.1016/j.meegid.2013.10.001


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