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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Ros3 (Lem3p/CDC50) Gene Dosage Is Implicated in Miltefosine Susceptibility in Leishmania (Viannia) braziliensis Clinical Isolates and in Leishmania (Leishmania) major

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Author(s):
Espada, Caroline R. [1] ; Albuquerque-Wendt, Andreia [2, 3, 4] ; Hornillos, Valentin [5, 6] ; Gluenz, Eva [2, 4] ; Coelho, Adriano C. [7] ; Uliana, Silvia R. B. [1]
Total Authors: 6
Affiliation:
[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Sao Paulo - Brazil
[2] Univ Oxford, Sir William Dunn Sch Pathol, Oxford - England
[3] Univ Lisbon, Inst Higiene & Med Trop, Global Hlth & Trop Med, Lisbon - Portugal
[4] Univ Glasgow, Coll Med Vet & Life Sci, Wellcome Ctr Integrat Parasitol, Inst Infect Immun & Inflammat, Glasgow, Lanark - Scotland
[5] Univ Seville, Dept Quim Organ, Seville - Spain
[6] Ctr Innovac Quim Avanzada, Seville - Spain
[7] Univ Estadual Campinas, Inst Biol, Dept Biol Anim, Campinas - Brazil
Total Affiliations: 7
Document type: Journal article
Source: ACS INFECTIOUS DISEASES; v. 7, n. 4, p. 849-858, APR 9 2021.
Web of Science Citations: 0
Abstract

The Ros3 protein is a component of the MT-Ros3 transporter complex, considered as the main route of miltefosine entry in Leishmania. L. braziliensis clinical isolates presenting differences in miltefosine susceptibility and uptake were previously shown to differentially express ros3. In this work, we showed that the ros3 gene copy number was increased in the isolate presenting the highest rates of miltefosine uptake and, thus, the highest susceptibility to this drug. The role of the ros3 gene dosage in miltefosine susceptibility was then investigated through a modulation of the gene copy number using two distinct approaches: through an overexpression of ros3 in a tolerant L. braziliensis clinical isolate and in L. major and by generating mono- and diallelic knockouts of this gene in L. major using clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 (Cas = CRISPR-associated). Although the levels of ros3 mRNA were increased at least 40-fold in overexpressing clones, no significant reduction in the half-maximal effective concentration (EC50) for miltefosine was observed in these parasites. The partial or complete deletion of ros3 in L. major, in turn, resulted in a significant increase of 3 and 20 times, respectively, in the EC50 to miltefosine. We unequivocally showed that the ros3 copy number is one of the factors involved in the differential susceptibility and uptake of miltefosine. (AU)

FAPESP's process: 15/09080-2 - Evaluation of candidate drugs for the treatment of Leishmaniasis in Brazil
Grantee:Silvia Reni Bortolin Uliana
Support Opportunities: Regular Research Grants
FAPESP's process: 18/25299-2 - Investigating the role of Ros3 in differential susceptibility of Leishmania to miltefosine using a CRISPR/Cas9 approach
Grantee:Caroline Ricce Espada
Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
FAPESP's process: 16/23405-4 - Susceptibility to miltefosine in Leishmania (Viannia) braziliensis clinical isolates: phenotypic characterization and investigation of the basis involved in reduced susceptibility to the drug
Grantee:Caroline Ricce Espada
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 16/21171-6 - Paromomycin for the treatment of Tegumentary Leishmaniasis: investigation in vitro, in vivo and in the identification of molecular markers associated with susceptibility and resistance
Grantee:Adriano Cappellazzo Coelho
Support Opportunities: Research Grants - Young Investigators Grants