Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole.
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.
Infection, Immunity, Injury and Repair Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Cheryl L
CL
Birmingham
Adam C
AC
Smith
Malina A
MA
Bakowski
Tamotsu
T
Yoshimori
John H
JH
Brumell
D000818:Animals; D001343:Autophagy; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism / Q000382:microbiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005347:Fibroblasts / Q000378:metabolism / Q000382:microbiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D012475:Salmonella / Q000378:metabolism / Q000502:physiology*; D012480:Salmonella Infections / Q000473:pathology*; D013997:Time Factors; D014162:Transfection; D014617:Vacuoles / Q000378:metabolism