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https://www.arca.fiocruz.br/handle/icict/55559
IN-DEPTH QUANTITATIVE PROTEOMICS CHARACTERIZATION OF IN VITRO SELECTED MILTEFOSINE RESISTANCE IN LEISHMANIA INFANTUM
FASP
Leishmania infantum
cytochrome c oxidase
fatty acid β-oxidation
mass spectrometry
miltefosine resistance
oxidative phosphorylation
quantitative proteomics
Author
Affilliation
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo de Genômica Funcional de Parasitos. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmanioses. Rio de Janeiro, RJ, Brazil/Rio de Janeiro Research Network on Neuroinflammation. Oswaldo Cruz Institute. Oswaldo Cruz Foundation. Rio de Janeiro, RJ, Brazil.
Biochemical Proteomics Group. Department of Proteomics and Signal Transduction. Max-Planck-Institute of Biochemistry. Planegg, Germany.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmanioses. Rio de Janeiro, RJ, Brazil/Rio de Janeiro Research Network on Neuroinflammation. Oswaldo Cruz Institute. Oswaldo Cruz Foundation. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmanioses. Rio de Janeiro, RJ, Brazil.
Research Center on Biological Chemistry. Federal University of São João Del Rei. Divinópolis, MG, Brazil.
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo de Genômica Funcional de Parasitos. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmanioses. Rio de Janeiro, RJ, Brazil/Rio de Janeiro Research Network on Neuroinflammation. Oswaldo Cruz Institute. Oswaldo Cruz Foundation. Rio de Janeiro, RJ, Brazil.
Biochemical Proteomics Group. Department of Proteomics and Signal Transduction. Max-Planck-Institute of Biochemistry. Planegg, Germany.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmanioses. Rio de Janeiro, RJ, Brazil/Rio de Janeiro Research Network on Neuroinflammation. Oswaldo Cruz Institute. Oswaldo Cruz Foundation. Rio de Janeiro, RJ, Brazil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Leishmanioses. Rio de Janeiro, RJ, Brazil.
Research Center on Biological Chemistry. Federal University of São João Del Rei. Divinópolis, MG, Brazil.
Fundação Oswaldo Cruz. Instituto René Rachou. Grupo de Genômica Funcional de Parasitos. Belo Horizonte, MG, Brazil.
Abstract
Visceral leishmaniasis (VL) is a neglected disease caused by Leishmania parasites. Although significant morbidity and mortality in tropical and subtropical regions of the world are associated with VL, the low investment for developing new treatment measures is chronic. Moreover, resistance and treatment failure are increasing for the main medications, but the emergence of resistance phenotypes is poorly understood at the protein level. Here, we analyzed the development of resistance to miltefosine upon experimental selection in a L. infantum strain. Time to miltefosine resistance emergence was ~six months and label-free quantitative mass-spectrometry-based proteomics analyses revealed that this process involves a remodeling of components of the membrane and mitochondrion, with significant increase in oxidative phosphorylation complexes, particularly on complex IV and ATP synthase, accompanied by increased energy metabolism mainly dependent on β-oxidation of fatty acids. Proteins canonically involved in ROS detoxification did not contribute to the resistant process whereas sterol biosynthesis enzymes could have a role in this development. Furthermore, changes in the abundance of proteins known to be involved in miltefosine resistance such as ABC transporters and phospholipid transport ATPase were detected. Together, our data show a more complete picture of the elements that make up the miltefosine resistance phenotype in L. infantum.
Keywords
ATP synthaseFASP
Leishmania infantum
cytochrome c oxidase
fatty acid β-oxidation
mass spectrometry
miltefosine resistance
oxidative phosphorylation
quantitative proteomics
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