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Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs

Alaridah, Nader LU ; Lutay, Nataliya LU ; Tenland, Erik LU ; Rönnholm, Anna LU ; Hallgren, Oskar LU ; Puthia, Manoj LU ; Westergren-Thorsson, Gunilla LU and Godaly, Gabriela LU (2017) In Journal of Innate Immunity 9. p.318-329
Abstract

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced... (More)

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Innate Immunity
volume
9
pages
318 - 329
publisher
Karger
external identifiers
  • scopus:85008401050
  • wos:000400923000009
ISSN
1662-811X
DOI
10.1159/000453454
language
English
LU publication?
yes
id
2f14e84b-6a0c-416a-93fd-17c56fa5361f
date added to LUP
2017-01-03 10:03:02
date last changed
2018-01-07 11:43:47
@article{2f14e84b-6a0c-416a-93fd-17c56fa5361f,
  abstract     = {<p>Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.</p>},
  author       = {Alaridah, Nader and Lutay, Nataliya and Tenland, Erik and Rönnholm, Anna and Hallgren, Oskar and Puthia, Manoj and Westergren-Thorsson, Gunilla and Godaly, Gabriela},
  issn         = {1662-811X},
  language     = {eng},
  pages        = {318--329},
  publisher    = {Karger},
  series       = {Journal of Innate Immunity},
  title        = {Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs},
  url          = {http://dx.doi.org/10.1159/000453454},
  volume       = {9},
  year         = {2017},
}