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J. Biol. Chem., Vol. 281, Issue 16, 11374-11383, April 21, 2006
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Autophagy Controls Salmonella Infection in Response to Damage to the Salmonella-containing Vacuole*
1123
From the
Infection, Immunity, Injury and Repair Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, the Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and the ¶Department of Cell Genetics, National Institute of Genetics, Yata 1111 Mishima, Shizuoka-ken 411-8540, Japan
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that causes disease in a variety of hosts. S. Typhimurium actively invade host cells and typically reside within a membrane-bound compartment called the Salmonella-containing vacuole (SCV). The bacteria modify the fate of the SCV using two independent type III secretion systems (TTSS). TTSS are known to damage eukaryotic cell membranes and S. Typhimurium has been suggested to damage the SCV using its Salmonella pathogenicity island (SPI)-1 encoded TTSS. Here we show that this damage gives rise to an intracellular bacterial population targeted by the autophagy system during in vitro infection. Approximately 20% of intracellular S. Typhimurium colocalized with the autophagy marker GFP-LC3 at 1 h postinfection. Autophagy of S. Typhimurium was dependent upon the SPI-1 TTSS and bacterial protein synthesis. Bacteria targeted by the autophagy system were often associated with ubiquitinated proteins, indicating their exposure to the cytosol. Surprisingly, these bacteria also colocalized with SCV markers. Autophagy-deficient (atg5-/-) cells were more permissive for intracellular growth by S. Typhimurium than normal cells, allowing increased bacterial growth in the cytosol. We propose a model in which the host autophagy system targets bacteria in SCVs damaged by the SPI-1 TTSS. This serves to retain intracellular S. Typhimurium within vacuoles early after infection to protect the cytosol from bacterial colonization. Our findings support a role for autophagy in innate immunity and demonstrate that Salmonella infection is a powerful model to study the autophagy process.
Received for publication, August 19, 2005 , and in revised form, January 18, 2006.
* This work was supported by an Investigators in Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. 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 Recipients of a University of Toronto Open Fellowship Award and studentships from the Natural Sciences and Engineering Research Council of Canada.
2 Supported by a studentship from the Research Training Centre, Hospital for Sick Children.
3 Recipient of the Premier's Research Excellence Award from the Ontario Ministry of Economic Development and Trade and the Boehringer Ingelheim (Canada) Young Investigator Award in Biological Sciences. To whom correspondence should be addressed: Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada. Tel.: 416-813-7654 (ext. 3555); Fax: 416-813-5028; E-mail: john.brumell{at}sickkids.ca.
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