Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake

Detalhes bibliográficos
Autor(a) principal: Espada, Caroline Ricce
Data de Publicação: 2019
Outros Autores: Magalhães, Rubens M, Cruz, Mario C, Machado, Paulo Roberto, Schriefer, Albert, Carvalho, Edgar Marcelino de, Hornillos, Valentín, Alves, João M., Cruz, Angela Kaysel, Coelho, Adriano Cappellazzo, Uliana, Silvia Reni Bortolin
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/35917
Resumo: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2011/20484-7 and 2015/09080-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 473343/2012-6), Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. SRBU is the recipient of a senior researcher scholarship from CNPq. ACC and CRE were fellows supported by FAPESP (2012/14629-5 and 2016/ 23405-4).
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spelling Espada, Caroline RicceMagalhães, Rubens MCruz, Mario CMachado, Paulo RobertoSchriefer, AlbertCarvalho, Edgar Marcelino deHornillos, ValentínAlves, João M.Cruz, Angela KayselCoelho, Adriano CappellazzoUliana, Silvia Reni Bortolin2019-09-26T13:29:49Z2019-09-26T13:29:49Z2019ESPADA, Caroline Ricce et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. IJP: Drugs and Drug Resistance, p. 1-9, Fev. 2019.2211-3207https://www.arca.fiocruz.br/handle/icict/3591710.1016/j.ijpddr.2019.02.005Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2011/20484-7 and 2015/09080-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 473343/2012-6), Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. SRBU is the recipient of a senior researcher scholarship from CNPq. ACC and CRE were fellows supported by FAPESP (2012/14629-5 and 2016/ 23405-4).Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. São Paulo, SP, Brasil.Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Centro de Facilidades para Apoio a Pesquisa. São Paulo, SP, Brasil.Universidade Federal da Bahia. Serviço de Imunologia. Salvador, BA, Brasil.Universidade Federal da Bahia. Instituto de Ciênicas da Saúde. Salvador, BA, Brasil.Universidade Federal da Bahia. Serviço de Imunologia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Universidad de Sevilla and Centro de Innovación en Química Avanzada.Departamento de Química Orgánica. Sevilla, Spain.Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. São Paulo, SP, Brasil.Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos. Ribeirão Preto, SP, Brasil.Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. São Paulo, SP, Brasil.In Brazil, cutaneous leishmaniasis is caused predominantly by L. (V.) braziliensis. The few therapeutic drugs available exhibit several limitations, mainly related to drug toxicity and reduced efficacy in some regions. Miltefosine (MF), the only oral drug available for leishmaniasis treatment, is not widely available and has not yet been approved for human use in Brazil. Our group previously reported the existence of differential susceptibility among L. (V.) braziliensis clinical isolates. In this work, we further characterized three of these isolates of L. (V.) braziliensis chosen because they exhibited the lowest and the highest MF half maximal inhibitory concentrations and were therefore considered less tolerant or more tolerant, respectively. Uptake of MF, and also of phosphocholine, were found to be significantly different in more tolerant parasites compared to the less sensitive isolate, which raised the hypothesis of differences in the MF transport complex Miltefosine Transporter (MT)-Ros3. Although some polymorphisms in those genes were found, they did not correlate with the drug susceptibility phenotype. Drug efflux and compartmentalization were similar in the isolates tested, and amphotericin B susceptibility was retained in MF tolerant parasites, suggesting that increased fitness was also not the basis of observed differences. Transcriptomic analysis revealed that Ros3 mRNA levels were upregulated in the sensitive strain compared to the tolerant ones. Increased mRNA abundance in more tolerant isolates was validated by quantitative PCR. Our results suggest that differential gene expression of the MT transporter complex is the basis of the differential susceptibility in these unselected, naturally occurring parasites.engElsevierLeishmania braziliensisIsoladosMiltefosineSuscetibilidadeCaptaçãoRNAseqLeishmania braziliensisIsolatesMiltefosineSusceptibilityUptakeRNAseqInvestigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptakeinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/35917/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALEspada R C Investigation of the pathways.pdfEspada R C Investigation of the 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dc.title.pt_BR.fl_str_mv Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
title Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
spellingShingle Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
Espada, Caroline Ricce
Leishmania braziliensis
Isolados
Miltefosine
Suscetibilidade
Captação
RNAseq
Leishmania braziliensis
Isolates
Miltefosine
Susceptibility
Uptake
RNAseq
title_short Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
title_full Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
title_fullStr Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
title_full_unstemmed Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
title_sort Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
author Espada, Caroline Ricce
author_facet Espada, Caroline Ricce
Magalhães, Rubens M
Cruz, Mario C
Machado, Paulo Roberto
Schriefer, Albert
Carvalho, Edgar Marcelino de
Hornillos, Valentín
Alves, João M.
Cruz, Angela Kaysel
Coelho, Adriano Cappellazzo
Uliana, Silvia Reni Bortolin
author_role author
author2 Magalhães, Rubens M
Cruz, Mario C
Machado, Paulo Roberto
Schriefer, Albert
Carvalho, Edgar Marcelino de
Hornillos, Valentín
Alves, João M.
Cruz, Angela Kaysel
Coelho, Adriano Cappellazzo
Uliana, Silvia Reni Bortolin
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Espada, Caroline Ricce
Magalhães, Rubens M
Cruz, Mario C
Machado, Paulo Roberto
Schriefer, Albert
Carvalho, Edgar Marcelino de
Hornillos, Valentín
Alves, João M.
Cruz, Angela Kaysel
Coelho, Adriano Cappellazzo
Uliana, Silvia Reni Bortolin
dc.subject.other.pt_BR.fl_str_mv Leishmania braziliensis
Isolados
Miltefosine
Suscetibilidade
Captação
RNAseq
topic Leishmania braziliensis
Isolados
Miltefosine
Suscetibilidade
Captação
RNAseq
Leishmania braziliensis
Isolates
Miltefosine
Susceptibility
Uptake
RNAseq
dc.subject.en.pt_BR.fl_str_mv Leishmania braziliensis
Isolates
Miltefosine
Susceptibility
Uptake
RNAseq
description Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2011/20484-7 and 2015/09080-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 473343/2012-6), Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. SRBU is the recipient of a senior researcher scholarship from CNPq. ACC and CRE were fellows supported by FAPESP (2012/14629-5 and 2016/ 23405-4).
publishDate 2019
dc.date.accessioned.fl_str_mv 2019-09-26T13:29:49Z
dc.date.available.fl_str_mv 2019-09-26T13:29:49Z
dc.date.issued.fl_str_mv 2019
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv ESPADA, Caroline Ricce et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. IJP: Drugs and Drug Resistance, p. 1-9, Fev. 2019.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/35917
dc.identifier.issn.pt_BR.fl_str_mv 2211-3207
dc.identifier.doi.none.fl_str_mv 10.1016/j.ijpddr.2019.02.005
identifier_str_mv ESPADA, Caroline Ricce et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. IJP: Drugs and Drug Resistance, p. 1-9, Fev. 2019.
2211-3207
10.1016/j.ijpddr.2019.02.005
url https://www.arca.fiocruz.br/handle/icict/35917
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
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