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J. Biol. Chem., Vol. 282, Issue 35, 25779-25789, August 31, 2007

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Exosomes Released from Infected Macrophages Contain Mycobacterium avium Glycopeptidolipids and Are Proinflammatory^*

From the Department of Biological Sciences, Center for Global Health and Infectious Diseases, University of Notre Dame, Notre Dame, Indiana 46556

Mycobacterium avium is a major opportunistic pathogen in HIV-positive individuals and is responsible for increased morbidity and mortality in AIDS patients. M. avium express glycopeptidolipids (GPLs) as a major cell wall constituent, and recent studies suggest that GPLs play an important role in M. avium pathogenesis. In the present study we show that M. avium-infected macrophages release GPLs, which are trafficked from the phagosome through the endocytic network to multivesicular bodies. Prior studies have shown that multivesicular bodies can fuse with the plasma membrane releasing small 50 to 100 nm vesicles known as exosomes. We found that M. avium-infected macrophages release exosomes containing GPLs leading to the transfer of GPLs from infected to uninfected macrophages. Interestingly, exosomes isolated from M. avium-infected but not from uninfected macrophages can stimulate a proinflammatory response in resting macrophages. This proinflammatory response is dependent on Toll like receptor (TLR) 2, TLR4, and MyD88 suggesting that released exosomes contain M. avium-expressed TLR ligands. Our studies are the first to demonstrate that exosomes isolated from mycobacteria-infected macrophages can induce a proinflammatory response, and we hypothesize that exosomes play an important role in immune surveillance during intracellular bacteria infections.

Received for publication, March 15, 2007 , and in revised form, June 13, 2007.

^* This work was supported by Grants AI056979 and AI052439 from the NIAID, National Institutes of Health (NIH). The H4A3, H4B4, 1D4B, and ABL2 monoclonal antibodies developed by J. Thomas August and James E. K. Hildreth were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD, NIH and maintained by the University of Iowa, Dept. of Biological Sciences. The anti-GPL antibodies were a generous gift from Patrick Brennan and John Spenser, Colorado State University. The M. avium 2151 strains were generously provided by John Belisle and Julia Inamine, Colorado State University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biology, University of Notre Dame, 130 Galvin Life Science Center, Notre Dame, IN 46556. Tel.: 574-631-3734; Fax: 574-631-7413; E-mail: Schorey.1{at}nd.edu.

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