Attaching and Effacing Bacterial Effector NleC Suppresses Epithelial Inflammatory Responses by Inhibiting NF-kappa B and p38 Mitogen-Activated Protein Kinase Activation

作者：Sham Ho Pan; Shames Stephanie R; Croxen Matthew A; Ma Caixia; Chan Justin M; Khan Mohammed A; Wickham Mark E; Deng Wanyin; Finlay B Brett; Vallance Bruce A^*

来源：Infection and Immunity, 2011, 79(9): 3552-3562.

DOI：10.1128/IAI.05033-11

Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli are noninvasive attaching and effacing (A/E) bacterial pathogens that cause intestinal inflammation and severe diarrheal disease. These pathogens utilize a type III secretion system to deliver effector proteins into host epithelial cells, modulating diverse cellular functions, including the release of the chemokine interleukin-8 (IL-8). While studies have implicated the effectors NleE (non-locus of enterocyte effacement [LEE]-encoded effector E) and NleH1 in suppressing IL-8 release, by preventing NF-kappa B nuclear translocation, the impact of these effectors only partially replicates the immunosuppressive actions of wild-type EPEC, suggesting another effector or effectors are involved. Testing an array of EPEC mutants, we identified the non-LEE-encoded effector C (NleC) as also suppressing IL-8 release. Infection by Delta nleC EPEC led to exaggerated IL-8 release from infected Caco-2 and HT-29 epithelial cells. NleC localized to EPEC-induced pedestals, with signaling studies revealing NleC inhibits both NF-kappa B and p38 mitogen-activated protein kinase (MAPK) activation. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that Delta nleC and wild-type C. rodentium-infected mice carried similar pathogen burdens, yet Delta nleC strain infection led to worsened colitis. Similarly, infection with Delta nleC C. rodentium in a cecal loop model induced significantly greater chemokine responses than infection with wild-type bacteria. These studies thus advance our understanding of how A/E pathogens subvert host inflammatory responses.

• 出版日期2011-9