Autophagy Controls Salmonella Infection in Response to Damage to the Salmonella-containing Vacuole*

By Cheryl L Birmingham, Adam C. Smith, M. Bakowski, T. Yoshimori, J. Brumell. Journal of Biological Chemistry, 2006

667 citations recorded by the source corpus.

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.

Subfields: Ecology, Endocrinology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/e70094c5127f9be06eb21ce59b2b5914bfb5bd02

How researchers see this paper

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In Ecology

1. V. Deretic

In Endocrinology

1. Beth Levine
2. V. Deretic
3. N. Mizushima

In Epidemiology

1. V. Deretic
2. D. Tang
3. R. Kang
4. Beth Levine
5. Michael Lotze
6. H. J. Zeh
7. I. Slaninová
8. Carolyn B. Coyne

Citations in the corpus

• History of lectins: from hemagglutinins to biological recognition molecules. (2004, background): “Microbes in damaged vesicles as well as microbes residing in the cytosol are targeted by the autophagy system that will engulf them in autophagosomes and restrict bacterial growth [67,68].”
• Autophagy in inflammation, infection, and immunometabolism (2021, positive): “This was soon followed by studies recognizing autophagy’s impact on Shigella (Ogawa et al., 2005), Salmonella (Birmingham et al., 2006), Crohn’s disease- Immunity.”
• PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity (2012, background): “A diverse array of pathogens interact with components of the autophagic pathway including Brucellus abortus (80, 81), Coxiella burnetii (82), Porphyromonas gingivalis (83), Salmonella enterica (84), Chlamydia trachomatis (85), Listeria monocytogenes (86), Group A Streptococcus (87, 88), Mycobacteriu”
• The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria (2009, background): “Typhimurium becomes poly-ubiquitin coated if released from SCV”
• WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1 (2014, background): “WIPI2b Is Required for LC3 Recruitment during Salmonella Infection Intracellular bacterial pathogens, such as Salmonella, are targeted by autophagy as part of a host cell bacterial clearance response (Birmingham et al., 2006).”
• Autophagy, Immunity, and Microbial Adaptations (2009, background): “…and DineshKumar, 2008 Salmonella enterica MEFs; epithelial cells Atg5 Atg5 deletion results in increased intracellular bacterial growth Birmingham et al., 2006 Shigella flexneri Dog kidney epithelial cells and MEFs Atg5 (in MEFs) IcsB mutant bacteria are targeted by autophagy, leading…”
• Toll‐like receptors control autophagy (2008, methodology): “HeLa cells were maintained in DMEM, 10% FBS. BMMs were derived from C57/BL6 mice or GFP–LC3 mice (Dr N Mizushima, Japan) as described previously (Via et al, 1998).”