FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis
- Autores
- Mondino, Sonia; Vazquez, Cristina Lourdes; Cabruja, Matias; Sala, Claudia; Cazenave-Gassiot, Amaury; Blanco, Federico Carlos; Wenk, Markus R.; Bigi, Fabiana; Cole, Stewart T.; Gramajo, Hugo; Gago, Gabriela
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection.
Instituto de Biotecnología
Fil: Mondino, Sonia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vazquez, Cristina Lourdes. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cabruja, Matias. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Sala, Claudia. Ecole Polytechnique Fédérale de Lausanne. Global Health Institute; Suiza
Fil: Cazenave-Gassiot, Amaury. National University of Singapore. Yong Loo Lin School of Medicine. Department of Biochemistry. Singapore Lipidomics Incubator; Singapur
Fil: Blanco, Federico Carlos. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Wenk, Markus R. National University of Singapore. Yong Loo Lin School of Medicine. Department of Biochemistry. Singapore Lipidomics Incubator; Singapur
Fil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de investigaciones Científicas y Tecnológicas; Argentina
Fil: Cole, Stewart T. Ecole Polytechnique Fédérale de Lausanne. Global Health Institute; Suiza
Fil: Gramajo, Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gago, Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina - Fuente
- Frontiers in Microbiology 11 : 586285 (Octubre 2020)
- Materia
-
Tuberculosis
Biosíntesis
Homeostasis
Virulencia
Mycobacterium tuberculosis
Biosynthesis
Virulence - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- http://creativecommons.org/licenses/by-nc-sa/4.0/
- Repositorio
- Institución
- Instituto Nacional de Tecnología Agropecuaria
- OAI Identificador
- oai:localhost:20.500.12123/8675
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FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosisMondino, SoniaVazquez, Cristina LourdesCabruja, MatiasSala, ClaudiaCazenave-Gassiot, AmauryBlanco, Federico CarlosWenk, Markus R.Bigi, FabianaCole, Stewart T.Gramajo, HugoGago, GabrielaTuberculosisBiosíntesisHomeostasisVirulenciaMycobacterium tuberculosisBiosynthesisVirulenceMycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection.Instituto de BiotecnologíaFil: Mondino, Sonia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vazquez, Cristina Lourdes. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cabruja, Matias. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sala, Claudia. Ecole Polytechnique Fédérale de Lausanne. Global Health Institute; SuizaFil: Cazenave-Gassiot, Amaury. National University of Singapore. Yong Loo Lin School of Medicine. Department of Biochemistry. Singapore Lipidomics Incubator; SingapurFil: Blanco, Federico Carlos. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wenk, Markus R. National University of Singapore. Yong Loo Lin School of Medicine. Department of Biochemistry. Singapore Lipidomics Incubator; SingapurFil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de investigaciones Científicas y Tecnológicas; ArgentinaFil: Cole, Stewart T. Ecole Polytechnique Fédérale de Lausanne. Global Health Institute; SuizaFil: Gramajo, Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gago, Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFrontiers Media2021-02-18T11:05:31Z2021-02-18T11:05:31Z2020-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://hdl.handle.net/20.500.12123/8675https://www.frontiersin.org/articles/10.3389/fmicb.2020.586285/full1664-302Xhttps://doi.org/10.3389/fmicb.2020.586285Frontiers in Microbiology 11 : 586285 (Octubre 2020)reponame:INTA Digital (INTA)instname:Instituto Nacional de Tecnología Agropecuariaenginfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)2025-09-29T13:45:08Zoai:localhost:20.500.12123/8675instacron:INTAInstitucionalhttp://repositorio.inta.gob.ar/Organismo científico-tecnológicoNo correspondehttp://repositorio.inta.gob.ar/oai/requesttripaldi.nicolas@inta.gob.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:l2025-09-29 13:45:08.397INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuariafalse |
dc.title.none.fl_str_mv |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
title |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
spellingShingle |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis Mondino, Sonia Tuberculosis Biosíntesis Homeostasis Virulencia Mycobacterium tuberculosis Biosynthesis Virulence |
title_short |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
title_full |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
title_fullStr |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
title_full_unstemmed |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
title_sort |
FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis |
dc.creator.none.fl_str_mv |
Mondino, Sonia Vazquez, Cristina Lourdes Cabruja, Matias Sala, Claudia Cazenave-Gassiot, Amaury Blanco, Federico Carlos Wenk, Markus R. Bigi, Fabiana Cole, Stewart T. Gramajo, Hugo Gago, Gabriela |
author |
Mondino, Sonia |
author_facet |
Mondino, Sonia Vazquez, Cristina Lourdes Cabruja, Matias Sala, Claudia Cazenave-Gassiot, Amaury Blanco, Federico Carlos Wenk, Markus R. Bigi, Fabiana Cole, Stewart T. Gramajo, Hugo Gago, Gabriela |
author_role |
author |
author2 |
Vazquez, Cristina Lourdes Cabruja, Matias Sala, Claudia Cazenave-Gassiot, Amaury Blanco, Federico Carlos Wenk, Markus R. Bigi, Fabiana Cole, Stewart T. Gramajo, Hugo Gago, Gabriela |
author2_role |
author author author author author author author author author author |
dc.subject.none.fl_str_mv |
Tuberculosis Biosíntesis Homeostasis Virulencia Mycobacterium tuberculosis Biosynthesis Virulence |
topic |
Tuberculosis Biosíntesis Homeostasis Virulencia Mycobacterium tuberculosis Biosynthesis Virulence |
dc.description.none.fl_txt_mv |
Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection. Instituto de Biotecnología Fil: Mondino, Sonia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vazquez, Cristina Lourdes. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cabruja, Matias. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sala, Claudia. Ecole Polytechnique Fédérale de Lausanne. Global Health Institute; Suiza Fil: Cazenave-Gassiot, Amaury. National University of Singapore. Yong Loo Lin School of Medicine. Department of Biochemistry. Singapore Lipidomics Incubator; Singapur Fil: Blanco, Federico Carlos. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Wenk, Markus R. National University of Singapore. Yong Loo Lin School of Medicine. Department of Biochemistry. Singapore Lipidomics Incubator; Singapur Fil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina. Consejo Nacional de investigaciones Científicas y Tecnológicas; Argentina Fil: Cole, Stewart T. Ecole Polytechnique Fédérale de Lausanne. Global Health Institute; Suiza Fil: Gramajo, Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gago, Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetics of Actinomycetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina |
description |
Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-10 2021-02-18T11:05:31Z 2021-02-18T11:05:31Z |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/20.500.12123/8675 https://www.frontiersin.org/articles/10.3389/fmicb.2020.586285/full 1664-302X https://doi.org/10.3389/fmicb.2020.586285 |
url |
http://hdl.handle.net/20.500.12123/8675 https://www.frontiersin.org/articles/10.3389/fmicb.2020.586285/full https://doi.org/10.3389/fmicb.2020.586285 |
identifier_str_mv |
1664-302X |
dc.language.none.fl_str_mv |
eng |
language |
eng |
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openAccess |
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http://creativecommons.org/licenses/by-nc-sa/4.0/ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) |
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application/pdf |
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Frontiers Media |
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Frontiers Media |
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Frontiers in Microbiology 11 : 586285 (Octubre 2020) reponame:INTA Digital (INTA) instname:Instituto Nacional de Tecnología Agropecuaria |
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