EPEC NleH1 is significantly more effective in reversing colitis and reducing mortality than NleH2 via differential effects on host signaling pathways

Sarah E. Kralicek, Mai Nguyen, Ki Jong Rhee, Rocio Tapia, Gail Hecht

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Enteropathogenic Escherichia coli (EPEC) is a foodborne pathogen that uses a type III secretion system to translocate effector molecules into host intestinal epithelial cells (IECs) subverting several host cell processes and signaling cascades. Interestingly, EPEC infection induces only modest intestinal inflammation in the host. The homologous EPEC effector proteins, NleH1 and NleH2, suppress the nuclear factor-κB (NF-κB) pathway and apoptosis in vitro. Increased apoptosis and activation of NF-κB and MAP kinases (MAPK) contribute to the pathogenesis of inflammatory bowel diseases (IBD). The aim of this study was to determine if NleH1 and NleH2 also block MAPK pathways in vitro and in vivo, and to compare the effects of these bacterial proteins on a murine model of colitis. Cultured IECs were infected with various strains of EPEC expressing NleH1 and NleH2, or not, and the activation of ERK1/2 and p38 was determined. In addition, the impact of infection with various strains of EPEC on murine DSS colitis was assessed by change in body weight, colon length, histology, and survival. Activation of apoptosis and MAPK signaling were also evaluated. Our data show that NleH1, but not NleH2, suppresses ERK1/2 and p38 activation in vitro. Interestingly, NleH1 affords significantly greater protection against and hastens recovery from dextran sodium sulfate (DSS)-induced colitis compared to NleH2. Strikingly, colitis-associated mortality was abolished by infection with EPEC strains expressing NleH1. Interestingly, in vivo NleH1 suppresses activation of ERK1/2 and p38 and blocks apoptosis independent of the kinase domain that inhibits NF-κB. In contrast, NleH2 suppresses only caspase-3 and p38, but not ERK1/2. We conclude that NleH1 affords greater protection against and improves recovery from DSS colitis compared to NleH2 due to its ability to suppress ERK1/2 in addition to NF-κB, p38, and apoptosis. These findings warrant further investigation of anti-inflammatory bacterial proteins as novel treatments for IBD.

Original languageEnglish
Pages (from-to)477-488
Number of pages12
JournalLaboratory Investigation
Issue number4
Publication statusPublished - 2018 Apr 1

Bibliographical note

Funding Information:
Acknowledgements We thank members of Hecht lab for providing invaluable comments. This research was supported by National Institutes of Health grant (DK097043 to G.H.) and the Department of Veterans Affairs (BX000785 and BX002687 to G.H.).

Publisher Copyright:
© 2018 United States & Canadian Academy of Pathology.

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology


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