Cargando…

Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection

Bacterial pathogens that infect phagocytic cells must deploy mechanisms that sense and neutralize host microbicidal effectors. For Mycobacterium tuberculosis, the causative agent of tuberculosis, these mechanisms allow the bacterium to rapidly adapt from aerosol transmission to initial growth in the...

Descripción completa

Detalles Bibliográficos
Autores principales: Buglino, John A, Sankhe, Gaurav D, Lazar, Nathaniel, Bean, James M, Glickman, Michael S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131098/
https://www.ncbi.nlm.nih.gov/pubmed/34003742
http://dx.doi.org/10.7554/eLife.65351
_version_ 1783694647318544384
author Buglino, John A
Sankhe, Gaurav D
Lazar, Nathaniel
Bean, James M
Glickman, Michael S
author_facet Buglino, John A
Sankhe, Gaurav D
Lazar, Nathaniel
Bean, James M
Glickman, Michael S
author_sort Buglino, John A
collection PubMed
description Bacterial pathogens that infect phagocytic cells must deploy mechanisms that sense and neutralize host microbicidal effectors. For Mycobacterium tuberculosis, the causative agent of tuberculosis, these mechanisms allow the bacterium to rapidly adapt from aerosol transmission to initial growth in the lung alveolar macrophage. Here, we identify a branched signaling circuit in M. tuberculosis that controls growth in the lung through integrated direct sensing of copper ions and nitric oxide by coupled activity of the Rip1 intramembrane protease and the PdtaS/R two-component system. This circuit uses a two-signal mechanism to inactivate the PdtaS/PdtaR two-component system, which constitutively represses virulence gene expression. Cu and NO inhibit the PdtaS sensor kinase through a dicysteine motif in the N-terminal GAF domain. The NO arm of the pathway is further controlled by sequestration of the PdtaR RNA binding response regulator by an NO-induced small RNA, controlled by the Rip1 intramembrane protease. This coupled Rip1/PdtaS/PdtaR circuit controls NO resistance and acute lung infection in mice by relieving PdtaS/R-mediated repression of isonitrile chalkophore biosynthesis. These studies identify an integrated mechanism by which M. tuberculosis senses and resists macrophage chemical effectors to achieve pathogenesis
format Online
Article
Text
id pubmed-8131098
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-81310982021-05-19 Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection Buglino, John A Sankhe, Gaurav D Lazar, Nathaniel Bean, James M Glickman, Michael S eLife Microbiology and Infectious Disease Bacterial pathogens that infect phagocytic cells must deploy mechanisms that sense and neutralize host microbicidal effectors. For Mycobacterium tuberculosis, the causative agent of tuberculosis, these mechanisms allow the bacterium to rapidly adapt from aerosol transmission to initial growth in the lung alveolar macrophage. Here, we identify a branched signaling circuit in M. tuberculosis that controls growth in the lung through integrated direct sensing of copper ions and nitric oxide by coupled activity of the Rip1 intramembrane protease and the PdtaS/R two-component system. This circuit uses a two-signal mechanism to inactivate the PdtaS/PdtaR two-component system, which constitutively represses virulence gene expression. Cu and NO inhibit the PdtaS sensor kinase through a dicysteine motif in the N-terminal GAF domain. The NO arm of the pathway is further controlled by sequestration of the PdtaR RNA binding response regulator by an NO-induced small RNA, controlled by the Rip1 intramembrane protease. This coupled Rip1/PdtaS/PdtaR circuit controls NO resistance and acute lung infection in mice by relieving PdtaS/R-mediated repression of isonitrile chalkophore biosynthesis. These studies identify an integrated mechanism by which M. tuberculosis senses and resists macrophage chemical effectors to achieve pathogenesis eLife Sciences Publications, Ltd 2021-05-18 /pmc/articles/PMC8131098/ /pubmed/34003742 http://dx.doi.org/10.7554/eLife.65351 Text en © 2021, Buglino et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Buglino, John A
Sankhe, Gaurav D
Lazar, Nathaniel
Bean, James M
Glickman, Michael S
Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection
title Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection
title_full Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection
title_fullStr Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection
title_full_unstemmed Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection
title_short Integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls M. tuberculosis acute lung infection
title_sort integrated sensing of host stresses by inhibition of a cytoplasmic two-component system controls m. tuberculosis acute lung infection
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131098/
https://www.ncbi.nlm.nih.gov/pubmed/34003742
http://dx.doi.org/10.7554/eLife.65351
work_keys_str_mv AT buglinojohna integratedsensingofhoststressesbyinhibitionofacytoplasmictwocomponentsystemcontrolsmtuberculosisacutelunginfection
AT sankhegauravd integratedsensingofhoststressesbyinhibitionofacytoplasmictwocomponentsystemcontrolsmtuberculosisacutelunginfection
AT lazarnathaniel integratedsensingofhoststressesbyinhibitionofacytoplasmictwocomponentsystemcontrolsmtuberculosisacutelunginfection
AT beanjamesm integratedsensingofhoststressesbyinhibitionofacytoplasmictwocomponentsystemcontrolsmtuberculosisacutelunginfection
AT glickmanmichaels integratedsensingofhoststressesbyinhibitionofacytoplasmictwocomponentsystemcontrolsmtuberculosisacutelunginfection