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Mycobacterial Induction of Autophagy Varies by Species and Occurs Independently of Mammalian Target of Rapamycin Inhibition*

Alfred J. Zullo,Sunhee Lee

Published 2012 in Journal of Biological Chemistry

ABSTRACT

Background: Induced mammalian target of rapamycin (mTOR)-dependent autophagy can restrict mycobacterial growth. Results: Mycobacterial lipids stimulate macrophage autophagy and mTOR signaling. Conclusion: Mycobacteria naturally induce autophagy in an mTOR-independent manner. Significance: This work will impact the development of therapeutic strategies for Mycobacteria tuberculosis infection. The interaction of host cells with mycobacteria is complex and can lead to multiple outcomes ranging from bacterial clearance to latent infection. Although many factors are involved, the mammalian autophagy pathway is recognized as a determinant that can influence the course of infection. Intervention aimed at utilizing autophagy to clear infection requires an examination of the autophagy and signal transduction induced by mycobacteria under native conditions. With both pathogenic and non-pathogenic mycobacteria, we show that infection correlates with an increase in the mammalian target of rapamycin (mTOR) activity indicating that autophagy induction by mycobacteria occurs in an mTOR-independent manner. Analysis of Mycobacterium smegmatis and Mycobacterium bovis bacille Calmette-Guérin (BCG), which respectively induce high and low autophagy responses, indicates that lipid material is capable of inducing both autophagy and mTOR signaling. Although mycobacterial infection potently induces mTOR activity, we confirm that bacterial viability can be reduced by rapamycin treatment. In addition, our work demonstrates that BCG can reduce autophagy responses to M. smegmatis suggesting that specific mechanisms are used by BCG to minimize host cell autophagy. We conclude that autophagy induction and mTOR signaling take place concurrently during mycobacterial infection and that host autophagy responses to any given mycobacterium stem from multiple factors, including the presence of activating macromolecules and inhibitory mechanisms.

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