title: Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs.
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 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.
authors.affiliation: Division of Laboratory Medicine, Department of MIG, Lund University, Lund, Sweden.
authors.forename: Nader
authors.initials: N
authors.lastname: Alaridah
authors.forename: Nataliya
authors.initials: N
authors.lastname: Lutay
authors.forename: Erik
authors.initials: E
authors.lastname: Tenland
authors.forename: Anna
authors.initials: A
authors.lastname: Rönnholm
authors.forename: Oskar
authors.initials: O
authors.lastname: Hallgren
authors.forename: Manoj
authors.initials: M
authors.lastname: Puthia
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westergren-Thorsson
authors.forename: Gabriela
authors.initials: G
authors.lastname: Godaly
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology; D014376:Tuberculosis / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014611:Vaccination; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma; D020830:rac1 GTP-Binding Protein
keywords: Bacille Calmette-Guérin; G-protein-coupled receptors; Pulmonary tuberculosis