title: Mycobacteria release active membrane  vesicles that modulate immune responses  in a TLR2-dependent manner in mice.
abstract: Bacteria naturally release membrane vesicles (MVs) under a variety of growth environments. Their production is associated with virulence due to their capacity to concentrate toxins and immunomodulatory molecules. In this report, we show that the 2 medically important species of mycobacteria, Mycobacterium tuberculosis and Mycobacterium bovis bacille Calmette-Guérin, release MVs when growing in both liquid culture and within murine phagocytic cells in vitro and in vivo. We documented MV production in a variety of virulent and nonvirulent mycobacterial species, indicating that release of MVs is a property conserved among mycobacterial species. Extensive proteomic analysis revealed that only MVs from the virulent strains contained TLR2 lipoprotein agonists. The interaction of MVs with macrophages isolated from mice stimulated the release of cytokines and chemokines in a TLR2-dependent fashion, and infusion of MVs into mouse lungs elicited a florid inflammatory response in WT but not TLR2-deficient mice. When MVs were administered to mice before M. tuberculosis pulmonary infection, an accelerated local inflammatory response with increased bacterial replication was seen in the lungs and spleens. Our results provide strong evidence that actively released mycobacterial vesicles are a delivery mechanism for immunologically active molecules that contribute to mycobacterial virulence. These findings may open up new horizons for understanding the pathogenesis of tuberculosis and developing vaccines.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York 10461, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Prados-Rosales
authors.forename: Andres
authors.initials: A
authors.lastname: Baena
authors.forename: Luis R
authors.initials: LR
authors.lastname: Martinez
authors.forename: Jose
authors.initials: J
authors.lastname: Luque-Garcia
authors.forename: Rainer
authors.initials: R
authors.lastname: Kalscheuer
authors.forename: Usha
authors.initials: U
authors.lastname: Veeraraghavan
authors.forename: Carmen
authors.initials: C
authors.lastname: Camara
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Jimenez
authors.forename: Aharona
authors.initials: A
authors.lastname: Glatman-Freedman
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology; D005260:Female; D008074:Lipoproteins / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008566:Membranes / Q000276:immunology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009163:Mycobacterium bovis / Q000276:immunology* / Q000648:ultrastructure; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity* / Q000648:ultrastructure; D040901:Proteomics; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000209:etiology / Q000276:immunology / Q000382:microbiology; D014774:Virulence / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2