Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-5 (of 5 Records) |
Query Trace: Vinayak S[original query] |
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Genetic variation in the Plasmodium falciparum circumsporozoite protein in India and its relevance to RTS,S malaria vaccine.
Zeeshan M , Alam MT , Vinayak S , Bora H , Tyagi RK , Alam MS , Choudhary V , Mittra P , Lumb V , Bharti PK , Udhayakumar V , Singh N , Jain V , Singh PP , Sharma YD . PLoS One 2012 7 (8) e43430 RTS,S is the most advanced malaria vaccine candidate, currently under phase-III clinical trials in Africa. This Plasmodium falciparum vaccine contains part of the central repeat region and the complete C-terminal T cell epitope region (Th2R and Th3R) of the circumsporozoite protein (CSP). Since naturally occurring polymorphisms at the vaccine candidate loci are critical determinants of the protective efficacy of the vaccines, it is imperative to investigate these polymorphisms in field isolates. In this study we have investigated the genetic diversity at the central repeat, C-terminal T cell epitope (Th2R and Th3R) and N-terminal T cell epitope regions of the CSP, in P. falciparum isolates from Madhya Pradesh state of India. These isolates were collected through a 5-year prospective study aimed to develop a well-characterized field-site for the future evaluation of malaria vaccine in India. Our results revealed that the central repeat (63 haplotypes, n = 161) and C-terminal Th2R/Th3R epitope (24 haplotypes, n = 179) regions were highly polymorphic, whereas N-terminal non-repeat region was less polymorphic (5 haplotypes, n = 161) in this population. We did not find any evidence of the role of positive natural selection in maintaining the genetic diversity at the Th2R/Th3R regions of CSP. Comparative analysis of the Th2R/Th3R sequences from this study to the global isolates (n = 1160) retrieved from the GenBank database revealed two important points. First, the majority of the sequences ( approximately 61%, n = 179) from this study were identical to the Dd2/Indochina type, which is also the predominant Th2R/Th3R haplotype in Asia ( approximately 59%, n = 974). Second, the Th2R/Th3R sequences in Asia, South America and Africa are geographically distinct with little allele sharing between continents. In conclusion, this study provides an insight on the existing polymorphisms in the CSP in a parasite population from India that could potentially influence the efficacy of RTS,S vaccine in this region. |
Selective sweeps and genetic lineages of Plasmodium falciparum drug -resistant alleles in Ghana.
Alam MT , de Souza DK , Vinayak S , Griffing SM , Poe AC , Duah NO , Ghansah A , Asamoa K , Slutsker L , Wilson MD , Barnwell JW , Udhayakumar V , Koram KA . J Infect Dis 2011 203 (2) 220-7 BACKGROUND: In 2005, Ghana adopted artemisinin-based combination therapy (ACT) for primary treatment of falciparum malaria. A comprehensive study of the drug-resistance-associated mutations and their genetic lineages will lead to a better understanding of the evolution of antimalarial drug resistance in this region. METHODS: The pfcrt, pfmdr1, dhps, and dhfr mutations associated with chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) resistance and the microsatellite loci flanking these genes were genotyped in Plasmodium falciparum isolates from Ghana. RESULTS: The prevalence of mutations associated with both CQ and SP resistance was high in Ghana. However, we observed a decrease in prevalence of the pfcrt K76T mutation in northern Ghana after the change in drug policy from CQ to ACT. Analysis of genetic diversity and differentiation at microsatellite loci flanking all 4 genes indicated that they have been under strong selection, because of CQ and SP use. The triple-mutant pfcrt and dhfr alleles in Ghana were derived from Southeast Asia, whereas the double-mutant dhfr, dhps, and pfmdr1 alleles were of African lineage. CONCLUSION: Because of the possible role of pfmdr1 in amodiaquine and mefloquine resistance, demonstrating selection on pfmdr1 and defining lineages of resistant alleles in an African population holds great importance. |
Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand
Alam MT , Vinayak S , Congpuong K , Wongsrichanalai C , Satimai W , Slutsker L , Escalante AA , Barnwell JW , Udhayakumar V . Antimicrob Agents Chemother 2010 55 (1) 155-64 The emergence and spread of drug resistant Plasmodium falciparum has been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4-5 times globally, including one origin on the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance conferring dihydropteroate synthase (dhps) alleles in Thailand. The dhps mutations and flanking microsatellite loci were genotyped in P. falciparum isolates collected from 11 Thai provinces along the Burma, Cambodia and Malaysia borders. Results indicated that resistant dhps alleles were fixed in Thailand, predominantly being the SGEGA, AGEAA and SGNGA triple mutants; and the AGKAA double mutant. These alleles had different geographical distributions. The SGEGA alleles were mostly found on the Burma border, while the SGNGA alleles occurred mainly on the Cambodia border and nearby provinces. Microsatellite data suggested that there were two major genetic lineages of the triple mutants in Thailand, one common for SGEGA/SGNGA alleles and another independent for AGEAA. Importantly, the newly reported SGNGA alleles have possibly originated on the Thailand-Cambodia border. All parasites in Yala province (Malaysia border) had AGKAA alleles with almost identical flanking microsatellites haplotypes. They were also identical at putatively neutral loci on chromosomes 2 and 3, suggesting clonal nature of the parasite population in Yala. In summary, this study suggests multiple and independent origins of the resistant dhps alleles in Thailand. |
Multiple genetic backgrounds of the amplified Plasmodium falciparum multidrug resistance (pfmdr1) gene and selective sweep of 184F mutation in Cambodia
Vinayak S , Alam MT , Sem R , Shah NK , Susanti AI , Lim P , Muth S , Maguire JD , Rogers WO , Fandeur T , Barnwell JW , Escalante AA , Wongsrichanalai C , Ariey F , Meshnick SR , Udhayakumar V . J Infect Dis 2010 201 (10) 1551-60 BACKGROUND: The emergence of artesunate-mefloquine (AS+MQ)-resistant Plasmodium falciparum in the Thailand-Cambodia region is a major concern for malaria control. Studies indicate that copy number increase and key alleles in the pfmdr1 gene are associated with AS+MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdr1 because of the spread of adaptive mutation and/or multiple copies of this gene in the P. falciparum population in Cambodia. METHODS: We characterized 13 microsatellite loci flanking (+/-99 kb) pfmdr1 in 93 single-clone P. falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdr1 gene. RESULTS: Genetic analysis revealed no difference in the mean (+/- standard deviation) expected heterozygosity (H(e)) at loci around single ([Formula: see text]) and multiple ([Formula: see text]) copies of pfmdr1. Evidence of genetic hitchhiking with the selective sweep of certain haplotypes was seen around mutant (184F) pfmdr1 allele, irrespective of the copy number. There was an overall reduction of 28% in mean H(e) (+/-SD) around mutant allele ([Formula: see text]), compared with wild-type allele ([Formula: see text]). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdr1 allele. CONCLUSION: The 184F mutant allele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds. |
Pfmdr1 amplification and fixation of chloroquine resistant pfcrt alleles in Venezuela
Griffing S , Syphard L , Sridaran S , McCollum AM , Mixson-Hayden T , Vinayak S , Villegas L , Barnwell JW , Escalante AA , Udhayakumar V . Antimicrob Agents Chemother 2010 54 (4) 1572-9 Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistant genotypes in some regions. In order to assess how historical drug policies impacted Venezuelan Plasmodium falciparum, we examined molecular changes to genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from 2003-2004 surveillance. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry and no evidence of strong selective pressure on mutations was found. Chloroquine resistant pfcrt alleles are fixed with two alleles: StctVMNT (91%) and SagtVMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes and multidrug resistant genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug resistant parasites. |
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