Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/35917
Title: Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake
Authors: 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
Affilliation: 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.
Abstract: 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.
Keywords: Leishmania braziliensis
Isolates
Miltefosine
Susceptibility
Uptake
RNAseq
keywords: Leishmania braziliensis
Isolados
Miltefosine
Suscetibilidade
Captação
RNAseq
Issue Date: 2019
Publisher: Elsevier
Citation: 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.
DOI: 10.1016/j.ijpddr.2019.02.005
ISSN: 2211-3207
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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