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
INTA Digital (INTA)
Institución
Instituto Nacional de Tecnología Agropecuaria
OAI Identificador
oai:localhost:20.500.12123/8675
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oai_identifier_str oai:localhost:20.500.12123/8675
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spelling 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)2025-10-23T11:17:30Zoai: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:l2025-10-23 11:17:30.303INTA 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
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Frontiers in Microbiology 11 : 586285 (Octubre 2020)
reponame:INTA Digital (INTA)
instname:Instituto Nacional de Tecnología Agropecuaria
reponame_str INTA Digital (INTA)
collection INTA Digital (INTA)
instname_str Instituto Nacional de Tecnología Agropecuaria
repository.name.fl_str_mv INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuaria
repository.mail.fl_str_mv tripaldi.nicolas@inta.gob.ar
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