FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis
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 defi...
| Autores principales: | , , , , , , , , , , |
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| Formato: | info:ar-repo/semantics/artículo |
| Lenguaje: | Inglés |
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Frontiers Media
2021
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| Materias: | |
| Acceso en línea: | 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 |
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| author | 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_browse | Bigi, Fabiana Blanco, Federico Carlos Cabruja, Matias Cazenave-Gassiot, Amaury Cole, Stewart T. Gago, Gabriela Gramajo, Hugo Mondino, Sonia Sala, Claudia Vazquez, Cristina Lourdes Wenk, Markus R. |
| 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_sort | Mondino, Sonia |
| collection | INTA Digital |
| 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. |
| format | info:ar-repo/semantics/artículo |
| id | INTA8675 |
| institution | Instituto Nacional de Tecnología Agropecuaria (INTA -Argentina) |
| language | Inglés |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Frontiers Media |
| publisherStr | Frontiers Media |
| record_format | dspace |
| spelling | INTA86752021-02-18T11:10:27Z FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis 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 Tuberculosis Biosíntesis Homeostasis Virulencia Mycobacterium tuberculosis Biosynthesis Virulence 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 2021-02-18T11:05:31Z 2021-02-18T11:05:31Z 2020-10 info:ar-repo/semantics/artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 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 eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-sa/4.0/ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) application/pdf Frontiers Media Frontiers in Microbiology 11 : 586285 (Octubre 2020) |
| spellingShingle | Tuberculosis Biosíntesis Homeostasis Virulencia Mycobacterium tuberculosis Biosynthesis Virulence 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 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 |
| 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_short | 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 |
| topic | Tuberculosis Biosíntesis Homeostasis Virulencia Mycobacterium tuberculosis Biosynthesis Virulence |
| 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 |
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