Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice

Rafael Prados-Rosales, Andres Baena, Luis R. Martinez, Jose Luque-Garcia, Rainer Kalscheuer, Usha Veeraraghavan, Carmen Camara, Joshua D. Nosanchuk, Gurdyal S. Besra, Bing Chen, Juan Jimenez, Aharona Glatman-Freedman, William R. Jacobs, Steven A. Porcelli, Arturo Casadevall

Research output: Contribution to journalArticle

135 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1471-1483
Number of pages13
JournalJournal of Clinical Investigation
Volume121
Issue number4
DOIs
StatePublished - Apr 1 2011

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Mycobacterium
Membranes
Mycobacterium tuberculosis
Lung
Virulence
Tuberculosis Vaccines
Phagocytes
Mycobacterium bovis
Chemokines
Proteomics
Lipoproteins
Spleen
Macrophages
Cytokines
Bacteria
Growth
Infection

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Prados-Rosales, R., Baena, A., Martinez, L. R., Luque-Garcia, J., Kalscheuer, R., Veeraraghavan, U., ... Casadevall, A. (2011). Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. Journal of Clinical Investigation, 121(4), 1471-1483. https://doi.org/10.1172/JCI44261

Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. / Prados-Rosales, Rafael; Baena, Andres; Martinez, Luis R.; Luque-Garcia, Jose; Kalscheuer, Rainer; Veeraraghavan, Usha; Camara, Carmen; Nosanchuk, Joshua D.; Besra, Gurdyal S.; Chen, Bing; Jimenez, Juan; Glatman-Freedman, Aharona; Jacobs, William R.; Porcelli, Steven A.; Casadevall, Arturo.

In: Journal of Clinical Investigation, Vol. 121, No. 4, 01.04.2011, p. 1471-1483.

Research output: Contribution to journalArticle

Prados-Rosales, R, Baena, A, Martinez, LR, Luque-Garcia, J, Kalscheuer, R, Veeraraghavan, U, Camara, C, Nosanchuk, JD, Besra, GS, Chen, B, Jimenez, J, Glatman-Freedman, A, Jacobs, WR, Porcelli, SA & Casadevall, A 2011, 'Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice', Journal of Clinical Investigation, vol. 121, no. 4, pp. 1471-1483. https://doi.org/10.1172/JCI44261
Prados-Rosales R, Baena A, Martinez LR, Luque-Garcia J, Kalscheuer R, Veeraraghavan U et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. Journal of Clinical Investigation. 2011 Apr 1;121(4):1471-1483. https://doi.org/10.1172/JCI44261
Prados-Rosales, Rafael ; Baena, Andres ; Martinez, Luis R. ; Luque-Garcia, Jose ; Kalscheuer, Rainer ; Veeraraghavan, Usha ; Camara, Carmen ; Nosanchuk, Joshua D. ; Besra, Gurdyal S. ; Chen, Bing ; Jimenez, Juan ; Glatman-Freedman, Aharona ; Jacobs, William R. ; Porcelli, Steven A. ; Casadevall, Arturo. / Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 4. pp. 1471-1483.
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