Khan Mohammed A, Ma Caixia, Knodler Leigh A, Valdez Yanet, Rosenberger Carrie M, Deng Wanyin, Finlay B Brett, Vallance Bruce A
Division of Gastroenterology, BC's Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada.
Infect Immun. 2006 May;74(5):2522-36. doi: 10.1128/IAI.74.5.2522-2536.2006.
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.
肠致病性大肠杆菌（EPEC）和肠出血性大肠杆菌（EHEC）是无创性细菌病原体，它们感染宿主的肠道上皮，导致严重的腹泻疾病。这些感染也会引起肠道炎症，尽管炎症反应的潜在机制及其在宿主防御中的作用尚不清楚。由于这些细菌是革兰氏阴性菌，Toll样受体4（TLR4）作为细菌脂多糖的天然受体可能参与宿主反应；然而，TLR4在胃肠道中的作用了解甚少，其对这类肠道细菌病原体的影响尚未得到验证。由于EPEC和EHEC具有人类特异性，我们用鼠柠檬酸杆菌感染小鼠，鼠柠檬酸杆菌是一种适应小鼠的黏附和抹除（A/E）细菌，它感染结肠上皮细胞，引起结肠炎和上皮增生，其使用的毒力蛋白与EPEC和EHEC相似。我们证明，鼠柠檬酸杆菌激活TLR4，并以部分依赖TLR4的方式在宿主细胞中迅速诱导NF-κB核易位。对TLR4缺陷小鼠的感染表明，TLR4依赖性反应介导了感染期间出现的大部分炎症和组织病理学变化，包括趋化因子MIP-2和MCP-1的诱导，以及巨噬细胞和中性粒细胞向感染肠道的募集。令人惊讶的是，在TLR4缺陷小鼠中，鼠柠檬酸杆菌在结肠中的传播延迟，而感染持续时间不受影响，这表明针对这种A/E病原体的TLR4介导反应对宿主没有保护作用，最终对宿主是适应不良的，导致了感染期间出现的发病率和病理学变化。
