Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice.
Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) are noninvasive bacterial pathogens that infect their hosts' intestinal epithelium, causing severe diarrheal disease. These infections also cause intestinal inflammation, although the mechanisms underlying the inflammatory response, as well as its potential role in host defense, are unclear. Since these bacteria are gram-negative, Toll-like receptor 4 (TLR4), the innate receptor for bacterial lipopolysaccharide may contribute to the host response; however, the role of TLR4 in the gastrointestinal tract is poorly understood, and its impact has yet to be tested against this family of enteric bacterial pathogens. Since EPEC and EHEC are human specific, we infected mice with Citrobacter rodentium, a mouse-adapted attaching and effacing (A/E) bacterium that infects colonic epithelial cells, causing colitis and epithelial hyperplasia, using a similar array of virulence proteins as EPEC and EHEC. We demonstrated that C. rodentium activates TLR4 and rapidly induced NF-kappaB nuclear translocation in host cells in a partially TLR4-dependent manner. Infection of TLR4-deficient mice revealed that TLR4-dependent responses mediate much of the inflammation and tissue pathology seen during infection, including the induction of the chemokines MIP-2 and MCP-1, as well as the recruitment of macrophages and neutrophils into the infected intestine. Surprisingly, spread of C. rodentium through the colon was delayed in TLR4-deficient mice, whereas the duration of the infection was unaffected, indicating that TLR4-mediated responses against this A/E pathogen are not host protective and are ultimately maladaptive to the host, contributing to both the morbidity and the pathology seen during infection.
Khan
Mohammed A
MA
Division of Gastroenterology, BC's Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada.
Ma
Caixia
C
Knodler
Leigh A
LA
Valdez
Yanet
Y
Rosenberger
Carrie M
CM
Deng
Wanyin
W
Finlay
B Brett
BB
Vallance
Bruce A
BA
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002432:Cecum / Q000276:immunology; D018925:Chemokines / Q000235:genetics; D044082:Citrobacter rodentium; D003092:Colitis / Q000209:etiology*; D003106:Colon / Q000382:microbiology / Q000473:pathology; D003967:Diarrhea / Q000209:etiology; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000032:analysis; D008198:Lymph Nodes / Q000382:microbiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D015431:Weight Loss
D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4