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

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Authors: Kralicek, S. E.; Nguyen, M.; Rhee, K. J.; Tapia, R; Hecht, G
Article Title: EPEC NleH1 is significantly more effective in reversing colitis and reducing mortality than NleH2 via differential effects on host signaling pathways
Abstract: 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-kappaB (NF-kappaB) pathway and apoptosis in vitro. Increased apoptosis and activation of NF-kappaB 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-kappaB. 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-kappaB, p38, and apoptosis. These findings warrant further investigation of anti-inflammatory bacterial proteins as novel treatments for IBD.
Journal Title: Laboratory investigation; a journal of technical methods and pathology
ISSN: 1530-0307; 0023-6837
Publisher: Unknown  
Journal Place: United States
Date Published: 2018
Language: eng
DOI/URL:

10.1038/s41374-017-0016-1
Notes: LR: 20180208; GR: R01 DK097043/DK/NIDDK NIH HHS/United States; GR: R56 DK050694/DK/NIDDK NIH HHS/United States; JID: 0376617; 2017/07/24 00:00 [received]; 2017/11/27 00:00 [accepted]; 2017/11/21 00:00 [revised]; 2018/02/04 06:00 [entrez]; 2018/02/06 06:00 [pubmed]; 2018/02/06 06:00 [medline]; aheadofprint