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

Abstract

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.

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

“…Accordingly, inflammatory CASP1 has been described to coordinate autophagy in response to L. pneumophila [24]. However, this is the first report of CASP4 deficiency negatively affecting autophagy in macrophages, which may explain the ability of other autophagy-interacting bacteria to be cleared in the presence of CASP4 [2,8,16]. In contrast, clearance of nonpathogenic E. coli does not depend on CASP1 or CASP4 [16,25].…”

“…The breakdown of damaged organelles and proteins via autophagy leads to the recycling of nutrients and sustains cellular energy levels. In addition, autophagy targets various intracellular pathogens such as Mycobacterium tuberculosis [1], Salmonella enterica serovar Typhimurium [2], Legionella pneumophila [3], Streptococcus pyogenes [4], and Burkholderia cenocepacia [5]. This bacteria-specific autophagic process, designated xenophagy, promotes bacterial clearance and prevents cellular escape.…”

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

“…The main role of autophagy is to eliminate unwanted cell constituents such as misfolded proteins, damaged organelles, and intracellular bacteria from the cell. [8][9][10] This allows the cell to maintain cellular homeostasis under stressful conditions including nutrient starvation. Autophagy also has a protective role against bacterial infection.…”

AMPK regulates autophagy by phosphorylating BECN1 at threonine 388

“…[1][2][3][4] Autophagy involves the sequestration of cytoplasmic "cargo" into a phagophore, which expands and matures into a double-membrane autophagosome; fusion of the latter with the lysosome exposes the engulfed cytoplamic material to lysosomal hydrolases for degradation and subsequent recycling. [5][6][7] More than 40 autophagy-related proteins have been identified in yeast and various mammalian species.…”