scholarly journals Reduced Polymorphism in the Kelch Propeller Domain in Plasmodium vivax Isolates from Cambodia

2014 ◽  
Vol 59 (1) ◽  
pp. 730-733 ◽  
Author(s):  
Jean Popovici ◽  
Sokheng Kao ◽  
Leanghor Eal ◽  
Sophalai Bin ◽  
Saorin Kim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Preliminary Data ◽  
Mutant Allele ◽  
Chloroquine Resistance ◽  
Wild Type ◽  
Nonsynonymous Mutation ◽  
Content Type

ABSTRACTPolymorphism in the ortholog gene of thePlasmodium falciparumK13 gene was investigated inPlasmodium vivaxisolates collected in Cambodia. All of them were Sal-1 wild-type alleles except two (2/284, 0.7%), andP. vivaxK12 polymorphism was reduced compared to that of theP. falciparumK13 gene. Both mutant allele isolates had the same nonsynonymous mutation at codon 552 (V552I) and were from Ratanak Kiri province. These preliminary data should encourage additional studies for associating artemisinin or chloroquine resistance and K12 polymorphism.

scholarly journals Molecular Characterization of the CytochromebGene andIn VitroAtovaquone Susceptibility of Plasmodium falciparum Isolates from Kenya

2015 ◽  
Vol 59 (3) ◽  
pp. 1818-1821 ◽  
Author(s):  
Luicer A. Ingasia ◽  
Hoseah M. Akala ◽  
Mabel O. Imbuga ◽  
Benjamin H. Opot ◽  
Fredrick L. Eyase ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Genetic Polymorphism ◽  
Molecular Characterization ◽  
Mutant Allele ◽  
Inhibitory Concentration ◽  
Wild Type Allele ◽  
Wild Type ◽  
Western Kenya ◽  
Content Type

ABSTRACTThe prevalence of a genetic polymorphism(s) at codon 268 in the cytochromebgene, which is associated with failure of atovaquone-proguanil treatment, was analyzed in 227Plasmodium falciparumparasites from western Kenya. The prevalence of the wild-type allele was 63%, and that of the Y268S (denoting a Y-to-S change at position 268) mutant allele was 2%. There were no pure Y268C or Y268N mutant alleles, only mixtures of a mutant allele(s) with the wild type. There was a correlation between parasite 50% inhibitory concentration (IC50) and parasite genetic polymorphism; mutant alleles had higher IC50s than the wild type.

scholarly journals In Vitroand Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

2015 ◽  
Vol 59 (12) ◽  
pp. 7540-7547 ◽  
Author(s):  
Naomi W. Lucchi ◽  
Franklin Komino ◽  
Sheila Akinyi Okoth ◽  
Ira Goldman ◽  
Philip Onyona ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Mutant Allele ◽  
Surveillance Program ◽  
Wild Type ◽  
Antimalarial Drug Resistance ◽  
Western Kenya ◽  
Content Type

ABSTRACTMalaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203Plasmodium falciparummalaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzedin vitrofor sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms inP. falciparum crt(Pfcrt),Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with thePfcrtwild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P< 0.0001), and higher proportions of parasites with elevated sensitivity to CQin vitro. The majority of isolates harbored the wild-type N allele inPfmdr-1codon 86 (93.5%), with only 7 (3.50%) samples with the N86Ymutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-typePfmdr-1D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Ymutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of thePfmdr-1gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.

scholarly journals Acquisition of the Ability To Assimilate Mannitol by Saccharomyces cerevisiae through Dysfunction of the General Corepressor Tup1-Cyc8

2014 ◽  
Vol 81 (1) ◽  
pp. 9-16 ◽  
Author(s):  
Moeko Chujo ◽  
Shiori Yoshida ◽  
Anri Ota ◽  
Kousaku Murata ◽  
Shigeyuki Kawai
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Molecular Basis ◽  
Mutant Allele ◽  
Wild Type ◽  
Growth Data ◽  
Content Type ◽  
Corepressor Complex ◽  
Marine Biomass ◽  
Prolonged Culture ◽  
Genes Encoding

ABSTRACTSaccharomyces cerevisiaenormally cannot assimilate mannitol, a promising brown macroalgal carbon source for bioethanol production. The molecular basis of this inability remains unknown. We found that cells capable of assimilating mannitol arose spontaneously from wild-typeS. cerevisiaeduring prolonged culture in mannitol-containing medium. Based on microarray data, complementation analysis, and cell growth data, we demonstrated that acquisition of mannitol-assimilating ability was due to spontaneous mutations in the genes encoding Tup1 or Cyc8, which constitute a general corepressor complex that regulates many kinds of genes. We also showed that anS. cerevisiaestrain carrying a mutant allele ofCYC8exhibited superior salt tolerance relative to other ethanologenic microorganisms; this characteristic would be highly beneficial for the production of bioethanol from marine biomass. Thus, we succeeded in conferring the ability to assimilate mannitol onS. cerevisiaethrough dysfunction of Tup1-Cyc8, facilitating production of ethanol from mannitol.

scholarly journals High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Johan Ursing ◽  
Lars Rombo ◽  
Staffan Eksborg ◽  
Lena Larson ◽  
Anita Bruvoll ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Standard Dose ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Chloroquine Resistance ◽  
High Dose ◽  
Qtc Interval ◽  
Content Type ◽  
Qt Interval Prolongation

ABSTRACT Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter (pfcrt) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 (P < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.)

scholarly journals Amplification ofpfmdr1,pfcrt,pvmdr1, and K13 Propeller Polymorphisms Associated with Plasmodium falciparum and Plasmodium vivax Isolates from the China-Myanmar Border

2015 ◽  
Vol 59 (5) ◽  
pp. 2554-2559 ◽  
Author(s):  
Jun Feng ◽  
Daili Zhou ◽  
Yingxue Lin ◽  
Huihui Xiao ◽  
He Yan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Vivax Malaria ◽  
Yunnan Province ◽  
Point Mutations ◽  
Border Region ◽  
Molecular Surveillance ◽  
Content Type ◽  
Antimalarial Resistance ◽  
Local Transmission

ABSTRACTMalaria in the China-Myanmar border region is still severe; local transmission of both falciparum and vivax malaria persists, and there is a risk of geographically expanding antimalarial resistance. In this research, thepfmdr1,pfcrt,pvmdr1, and K13-propeller genotypes were determined in 26Plasmodium falciparumand 64Plasmodium vivaxisolates from Yingjiang county of Yunnan province. Thepfmdr1(11.5%),pfcrt(34.6%), andpvmdr1(3.1%) mutations were prevalent at the China-Myanmar border. The indigenous samples exhibited prevalences of 14.3%, 28.6%, and 14.3% forpfmdr1N86Y,pfcrtK76T, andpfcrtM74I, respectively, whereas the samples from Myanmar showed prevalences of 10.5%, 21.1%, and 5.3%, respectively. The most prevalent genotypes ofpfmdr1andpfcrtwere Y86Y184and M74N75T76, respectively. Nopvmdr1mutation occurred in the indigenous samples but was observed in two cases coming from Myanmar. In addition, we are the first to report on 10 patients (38.5%) with five different K13 point mutations. The F446I allele is predominant (19.2%), and its prevalence was 28.6% in the indigenous samples of Yingjiang county and 15.8% in samples from Myanmar. The present data might be helpful for enrichment of the molecular surveillance of antimalarial resistance and useful for developing and updating guidance for the use of antimalarials in this region.

scholarly journals Antibodies to a Single, Conserved Epitope in Anopheles APN1 Inhibit Universal Transmission of Plasmodium falciparum and Plasmodium vivax Malaria

2013 ◽  
Vol 82 (2) ◽  
pp. 818-829 ◽  
Author(s):  
Jennifer S. Armistead ◽  
Isabelle Morlais ◽  
Derrick K. Mathias ◽  
Juliette G. Jardim ◽  
Jaimy Joy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Content Type ◽  
Block Transmission ◽  
Antibody Recognition ◽  
Protective Epitope ◽  
Product Profile ◽  
Plasmodium Vivax Malaria ◽  
Transmission Blocking Vaccines ◽  
Conserved Epitope

ABSTRACTMalaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of thePlasmodiumparasite, theAnophelesmosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission ofPlasmodium falciparumandPlasmodium vivaxacross distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria.

scholarly journals Saquinavir Inhibits the Malaria Parasite's Chloroquine Resistance Transporter

2012 ◽  
Vol 56 (5) ◽  
pp. 2283-2289 ◽  
Author(s):  
Rowena E. Martin ◽  
Alice S. Butterworth ◽  
Donald L. Gardiner ◽  
Kiaran Kirk ◽  
James S. McCarthy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Heterologous Expression ◽  
Protease Inhibitors ◽  
Chloroquine Resistance ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
Resistant Phenotype ◽  
Transgenic Parasites

ABSTRACTThe antiretroviral protease inhibitors (APIs) ritonavir, saquinavir, and lopinavir, used to treat HIV infection, inhibit the growth ofPlasmodium falciparumat clinically relevant concentrations. Moreover, it has been reported that these APIs potentiate the activity of chloroquine (CQ) against this parasitein vitro. The mechanism underlying this effect is not understood, but the degree of chemosensitization varies between the different APIs and, with the exception of ritonavir, appears to be dependent on the parasite exhibiting a CQ-resistant phenotype. Here we report a study of the role of theP. falciparumchloroquine resistance transporter (PfCRT) in the interaction between CQ and APIs, using transgenic parasites expressing different PfCRT alleles and using theXenopus laevisoocyte system for the heterologous expression of PfCRT. Our data demonstrate that saquinavir behaves as a CQ resistance reverser and that this explains, at least in part, its ability to enhance the effects of CQ in CQ-resistantP. falciparumparasites.

scholarly journals Molecular Epidemiology of Plasmodium falciparum Chloroquine Resistance Transporter Genes among School Children in Kwara State, Southwestern Nigeria

2020 ◽  
pp. 1-12
Author(s):  
A. O. Oluwasogo ◽  
H. O. Ismail ◽  
D. A. Pelumi
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Chloroquine Resistance ◽  
Fixation Method ◽  
Age Group ◽  
Wild Type ◽  
School Students ◽  
Southwestern Nigeria ◽  
Parasite Count ◽  
Chloroquine Resistance Transporter

Background: Plasmodium falciparum existence continues to develop resistance to conventional antimalaria drugs in malaria endemic areas. Plasmodia often prevent drugs from interacting with the target site, hence, developing resistance to antimalaria drugs. Mutations in the Plasmodium falciparum chloroquine resistance transporter (Pfcrt), are the major determinant of chloroquine resistance in human malaria parasite. Methodology: Malaria infection, Pfcrt and Pfmdr1 genes of isolates among school students within the age range of 11-22 years from four selected rural communities of Kwara state were studied. One hundred and eighty seven subjects (187) were selected for the study. Blood samples were collected by finger prick method for malaria screening. Nested PCR and restriction fragment length polymorphism (RFLP) were done to detect alleles of pfcrt at codon 76 and pfmdr1 at codon 86. DNA of isolates was appropriately extracted from the filter paper blots using the methanol fixation method. Logistic regression was performed on the binary observations obtained while linear regression was conducted on the fifty (50) subjects that tested positive to malaria. Results: Out of 187 subjects screened, 26.7% (50) were positive to P. falciparum. Highest malaria parasite count of 36.4% was recorded in 14-16 years age group while 20-22 years age group had the least malaria parasite count (15.4%). The result of the studied isolates indicated that out of 50 isolates analyzed for Pfcrt gene, wild type alleles accounted for 32% (16) while mutant alleles accounted for 68% (34). Alakuko Community accounted for the least number of T76 mutant alleles 10% (5) while Apado community recorded the highest number of T76 mutant gene 22% (11). For Pfmdr1 gene analysis at codon 86, isolates from Apado community showed the highest mutant type alleles (Y86) of 22% (11), while Igbonla community in Ifelodun local government had the least mutant alleles, 6% (3). Conclusion: The overall result revealed existence of mutant alleles in both the Pfcrt and Pfmdr1 genes which was higher than the wild type gene in both cases. The presence of chloroquine resistance genes among the studied population implies that alternative antimalaria drugs should be designed by pharmaceutical industry.

scholarly journals Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Catherine J. Mitran ◽  
Angie Mena ◽  
Sedami Gnidehou ◽  
Shanna Banman ◽  
Eliana Arango ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Vivax ◽  
Molecular Mechanism ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Placental Malaria ◽  
Content Type ◽  
Heterologous Immunity ◽  
Cryptic Epitopes

ABSTRACT Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro. The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes. IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium. Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.

scholarly journals Genotypes and phenotypes of resistance in Ecuadorian Plasmodium falciparum

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Gabriela Valenzuela ◽  
L. Enrique Castro ◽  
Julio Valencia-Zamora ◽  
Claudia A. Vera-Arias ◽  
Petra Rohrbach ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Chloroquine Resistance ◽  
In Vitro Assays ◽  
Wild Type ◽  
The Status ◽  
Transport Assay ◽  
Resistance Markers

Abstract Background Malaria continues to be endemic in the coast and Amazon regions of Ecuador. Clarifying current Plasmodium falciparum resistance in the country will support malaria elimination efforts. In this study, Ecuadorian P. falciparum parasites were analysed to determine their drug resistance genotypes and phenotypes. Methods Molecular analyses were performed to search for mutations in known resistance markers (Pfcrt, Pfdhfr, Pfdhps, Pfmdr1, k13). Pfmdr1 copy number was determined by qPCR. PFMDR1 transporter activity was characterized in live parasites using live cell imaging in combination with the Fluo-4 transport assay. Chloroquine, quinine, lumefantrine, mefloquine, dihydroartemisinin, and artemether sensitivities were measured by in vitro assays. Results The majority of samples from this study presented the CVMNT genotype for Pfcrt (72–26), NEDF SDFD mutations in Pfmdr1 and wild type genotypes for Pfdhfr, Pfdhps and k13. The Ecuadorian P. falciparum strain ESM-2013 showed in vitro resistance to chloroquine, but sensitivity to quinine, lumefantrine, mefloquine, dihydroartemisinin and artemether. In addition, transport of the fluorochrome Fluo-4 from the cytosol into the digestive vacuole (DV) of the ESM-2013 strain was minimally detected in the DV. All analysed samples revealed one copy of Pfmdr1. Conclusion This study indicates that Ecuadorian parasites presented the genotype and phenotype for chloroquine resistance and were found to be sensitive to SP, artemether-lumefantrine, quinine, mefloquine, and dihydroartemisinin. The results suggest that the current malaria treatment employed in the country remains effective. This study clarifies the status of anti-malarial resistance in Ecuador and informs the P. falciparum elimination campaigns in the country.

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