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J. Biol. Chem., Vol. 282, Issue 4, 2695-2706, January 26, 2007

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Staphylococcus aureus Subvert Autophagy for Induction of Caspase-independent Host Cell Death^*

Annabelle Schnaith, Hamid Kashkar, Sonja A. Leggio, Klaus Addicks^¶, Martin Krönke, and Oleg Krut¹

From the Institute for Medical Microbiology, Immunology and Hygiene, Center for Molecular Medicine Cologne, and ^¶Department for Anatomy I, University of Cologne, 50935 Cologne, Germany

Staphylococcus aureus is a common bacterial etiology of serious infectious diseases. S. aureus can invade various types of non-professional phagocytes to produce host cell death. We show here that shortly after invasion of HeLa cells S. aureus transit to autophagosomes was characterized by double membranes and co-localization with LC3. S. aureus were not able to replicate and produce cell death in autophagy-deficient atg5^-/- mouse embryonic fibroblasts. S. aureus-containing autophagosomes do not acidify nor do they acquire lysosome-associated membrane protein-2, indicating that S. aureus inhibits autophagosome maturation and fusion with lysosomes. Eventually, S. aureus escape from autophagosomes into the cytoplasm, which results in caspase-independent host cell death. S. aureus strains deficient for agr, a global regulator of S. aureus virulence, were not targeted by autophagy and did not produce host-cell death. Autophagy induction by rapamycin restored both replication and cytotoxicity of agr-deficient S. aureus strains, indicating that an agr-regulated factor(s) is required for autophagy-mediated cytotoxicity. The results of this study suggest that rapid induction of autophagy is essential for S. aureus replication, escape into the cytoplasm, and host cell killing.

Received for publication, October 17, 2006 , and in revised form, November 14, 2006.

^* This work was supported by the Deutsche Forschungsgemeinschaf Grant SFB 670. 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: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Cologne, Germany. Tel.: 49-22147832103; Fax: 49-22147832134; E-mail: oleg.krut{at}uni-koeln.de.

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