Abstract
Enterohemorrhagic Escherichia coli serotype O157:H7 is a food borne enteric bacterial pathogen that causes significant morbidity and mortality in both developing and industrialized nations. E. coli O157:H7 infection of host epithelial cells inhibits the interferon gamma pro-inflammatory signaling pathway, which is important for host defense against microbial pathogens, through the inhibition of Stat-1 tyrosine phosphorylation. The aim of this study was to determine which bacterial factors are involved in the inhibition of Stat-1 tyrosine phosphorylation. Human epithelial cells were challenged with either live bacteria or bacterial-derived culture supernatants, stimulated with interferon-gamma, and epithelial cell protein extracts were then analyzed by immunoblotting. The results show that Stat-1 tyrosine phosphorylation was inhibited by E. coli O157:H7 secreted proteins. Using sequential anion exchange and size exclusion chromatography, YodA was identified, but not confirmed to mediate subversion of the Stat-1 signaling pathway using isogenic mutants. We conclude that E. coli O157:H7 subverts Stat-1 tyrosine phosphorylation in response to interferon-gamma through a still as yet unidentified secreted bacterial protein.
Highlights
Enterohemorrhagic Escherichia coli (EHEC), including the most common serotype O157:H7, is a non-invasive enteric bacterial pathogen that causes both sporadic cases and outbreaks of hemorrhagic colitis and hemolytic-uremic syndrome in humans [1]
This activation leads to signal transducer and activator of transcription-1 (Stat-1) dimerization and translocation from the cytosol into the nucleus, where it binds to the gamma activating sequence (GAS) and triggers the up-regulation of up to 2,000 proinflammatory genes, including inducible nitric oxide synthase, monocyte chemoattractant protein-1 (MCP-1) and lymphocyte adhesion protein ICAM-1 [5]
IFNc mediated Stat-1 tyrosine phosphorylation [9,13-Submitted], indicating that the ability to subvert IFNc signaling is a specific ability of EHEC, and not all pathogenic E. coli
Summary
Enterohemorrhagic Escherichia coli (EHEC), including the most common serotype O157:H7, is a non-invasive enteric bacterial pathogen that causes both sporadic cases and outbreaks of hemorrhagic colitis and hemolytic-uremic syndrome in humans [1]. IFNc production by macrophages, Natural Killer (NK) T cells and activated T cells triggers an antimicrobial state in host cells by binding to the IFNc receptor, and tyrosine phosphorylation of the signal transducer and activator of transcription-1 (Stat-1) molecule. This activation leads to Stat-1 dimerization and translocation from the cytosol into the nucleus, where it binds to the gamma activating sequence (GAS) and triggers the up-regulation of up to 2,000 proinflammatory genes, including inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1) and lymphocyte adhesion protein ICAM-1 [5]. An intact IFNc pathway is essential to combat infection initiated from a wide range of microbial pathogens; patients with genetic defects in Stat-1 signaling are susceptible to microbial infections [6,7,8]
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