Point mutations in FimH adhesin of Crohn's disease-associated adherent-invasive Escherichia coli enhance intestinal inflammatory response.
Point mutations in FimH adhesin of Crohn's disease-associated adherent-invasive Escherichia coli enhance intestinal inflammatory response.
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DOI：
10.1371/journal.ppat.1003141
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Barnich N
中科院分区：
文献类型：
--
作者：
Dreux N;Denizot J;Martinez-Medina M;Mellmann A;Billig M;Kisiela D;Chattopadhyay S;Sokurenko E;Neut C;Gower-Rousseau C;Colombel JF;Bonnet R;Darfeuille-Michaud A;Barnich N
粘附-侵袭性大肠杆菌（AIEC）在克罗恩病（CD）回肠粘膜上异常占优势。AIEC参考菌株LF82通过常见的1型毛粘连素FimH粘附回肠细胞，识别CD回肠上皮细胞异常表达的CEACAM6受体。对45株AIEC和47株非AIEC菌株的fimH基因进行了测序。基于fimH DNA序列的系统发育树表明，AIEC菌株主要表达fimH，并伴有近期进化起源的氨基酸突变，这是细菌病原体病理适应性变化的典型特征。fim的点突变，一些独特的AIEC相关性质，赋予AIEC细菌粘附表达ceacam的T84肠上皮细胞显著更高的能力。此外，在LF82菌株中，将fimH LF82（表达aiec相关突变的fimH）替换为fimH K12（表达共生大肠杆菌K12的fimH），降低了细菌在表达人CEACAM受体的感染CEABAC10转基因小鼠中持续存在和诱导严重结肠炎和肠道炎症的能力。我们的研究结果强调了AIEC毒力进化的机制，该机制涉及常见细菌特征（如FimH蛋白）中氨基酸突变的选择，并导致遗传易感宿主的慢性炎症性肠病（IBD）的发展。fimH snp分析可能是预测IBD患者分离的大肠杆菌潜在毒力的一种有用的方法，可用于诊断或流行病学研究，并确定新的治疗干预策略，以阻断IBD早期AIEC与肠道黏膜之间的相互作用。炎症性肠病的病因学，特别是克罗恩病（CD），涉及宿主遗传因素和肠道微生物群的紊乱。粘附-侵袭性大肠杆菌（AIEC）正受到越来越多的关注，因为在世界范围内，它们在乳糜泻患者中比在健康受试者中更普遍。AIEC通过1型菌毛粘附在回肠肠细胞上，而1型菌毛可识别CEACAM6受体，而CEACAM6受体在CD患者中异常表达。AIEC粘附在表达CEACAM6的肠上皮细胞上的能力可能与1型菌毛FimH粘附素亚基中氨基酸替换的存在有关。AIEC菌株表达具有新近获得的氨基酸突变的FimH蛋白变体，这是细菌病原体病理适应进化的典型特征。AIEC相关的FimH突变使AIEC细菌粘附表达ceacam的肠上皮细胞的能力显著提高。我们的研究结果强调了AIEC致病进化的机制，涉及AIEC肠道定植所需的FimH致病适应性突变的选择，这导致了AIEC在遗传易感宿主中的慢性炎症的发展。fimH snp分析可能是流行病学研究中预测IBD患者分离的大肠杆菌潜在毒力和开发新的治疗干预措施的有用方法。
Adherent-invasive Escherichia coli (AIEC) are abnormally predominant on Crohn's disease (CD) ileal mucosa. AIEC reference strain LF82 adheres to ileal enterocytes via the common type 1 pili adhesin FimH and recognizes CEACAM6 receptors abnormally expressed on CD ileal epithelial cells. The fimH genes of 45 AIEC and 47 non-AIEC strains were sequenced. The phylogenetic tree based on fimH DNA sequences indicated that AIEC strains predominantly express FimH with amino acid mutations of a recent evolutionary origin - a typical signature of pathoadaptive changes of bacterial pathogens. Point mutations in FimH, some of a unique AIEC-associated nature, confer AIEC bacteria a significantly higher ability to adhere to CEACAM-expressing T84 intestinal epithelial cells. Moreover, in the LF82 strain, the replacement of fimH LF82 (expressing FimH with an AIEC-associated mutation) with fimH K12 (expressing FimH of commensal E. coli K12) decreased the ability of bacteria to persist and to induce severe colitis and gut inflammation in infected CEABAC10 transgenic mice expressing human CEACAM receptors. Our results highlight a mechanism of AIEC virulence evolution that involves selection of amino acid mutations in the common bacterial traits, such as FimH protein, and leads to the development of chronic inflammatory bowel disease (IBD) in a genetically susceptible host. The analysis of fimH SNPs may be a useful method to predict the potential virulence of E. coli isolated from IBD patients for diagnostic or epidemiological studies and to identify new strategies for therapeutic intervention to block the interaction between AIEC and gut mucosa in the early stages of IBD. The etiology of inflammatory bowel diseases, in particular Crohn's disease (CD), involves disorders in host genetic factors and intestinal microbiota. Adherent-invasive Escherichia coli (AIEC) are receiving increasing attention because they have been reported worldwide to be more prevalent in CD patients than in healthy subjects. AIEC adhere to ileal enterocytes via type 1 pili, which recognize the CEACAM6 receptor, which is abnormally expressed in CD patients. The ability of AIEC to adhere to intestinal epithelial cells expressing CEACAM6 could be correlated with the presence of amino acid substitutions in the type 1 pili FimH adhesin subunit. AIEC strains express FimH protein variants with recently acquired amino acid mutations, which is a typical signature of pathoadaptive evolution of bacterial pathogens. AIEC-associated mutations in FimH confer on AIEC bacteria a significantly higher ability to adhere to CEACAM-expressing intestinal epithelial cells. Our results highlight a mechanism of AIEC pathogenic evolution that involves selection of FimH pathoadaptive mutations, which are required for AIEC gut colonization, which leads to the development of chronic inflammation in a genetically susceptible host. The analysis of fimH SNPs may be a useful method to predict the potential virulence of E. coli isolated from IBD patients in epidemiological studies and to develop new therapeutic interventions.
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影响因子：
11.3
作者：
Hannan TJ;Totsika M;Mansfield KJ;Moore KH;Schembri MA;Hultgren SJ
通讯作者：
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作者：
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29.4
作者：
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影响因子：
3.6
作者：
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Hultgren, SJ