TY - JOUR
T1 - Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice
AU - Prados-Rosales, Rafael
AU - Baena, Andres
AU - Martinez, Luis R.
AU - Luque-Garcia, Jose
AU - Kalscheuer, Rainer
AU - Veeraraghavan, Usha
AU - Camara, Carmen
AU - Nosanchuk, Joshua D.
AU - Besra, Gurdyal S.
AU - Chen, Bing
AU - Jimenez, Juan
AU - Glatman-Freedman, Aharona
AU - Jacobs, William R.
AU - Porcelli, Steven A.
AU - Casadevall, Arturo
PY - 2011/4/1
Y1 - 2011/4/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI44261
DO - 10.1172/JCI44261
M3 - Article
C2 - 21364279
AN - SCOPUS:79953304475
SN - 0021-9738
VL - 121
SP - 1471
EP - 1483
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -