Genome Analysis of Emergence Mechanisms of New Enterohemorrhagic Escherichia coli and Genome-Based Drug Research toward HUS Treatment

新型肠出血性大肠杆菌发生机制的基因组分析及治疗 HUS 的基因组药物研究

• 批准号: 16390128
• 负责人: YAMAMOTO Tatsuo
• 金额: $ 9.6万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390128/
• 关键词: Enterohemorrhagic Escherichia coli (EHEC); HUS; Genome analysis; WIM model; Adherence factor; IgA1 protease; 腸管出血性大腸菌(EHEC); 溶血性尿毒症症候群(HUS); タイプIII分泌システム; 血清型O86; 粘着性プラスミド; 志賀毒素ファージ; アニソダミン

Infection of children and the elderly with enterohemorrhagic Escherichia coli (EHEC) results in hemolytic uremic syndrome (HUS), a severe complication with a poor prognosis. The type III secretion system (mechanism of intestinal colonization) of EHEC has been considered to be essential for the development of HUS. However, in case of intrafamilinal infection due to serotype O86 EHEC, although the E.coli strains do not have the type III secretion system, infected children developed HUS, and died. In this study, we investigated the molecular genetic properties of serotype O86 EHEC strains. These strains had a 120.73-kb plasmid (pO86A) encoding a diffuse adherence factor (HdaA), and lysogenized a 60.238-kb phage encoding type 2 Shiga toxin (Stx2). pO86A also had the Shigella flexneri type IgA1 protease gene, and conferred resistance to mucosal immunity to serotype O86 EHEC strains. The Stx phage showed properties of the insertion site found only in O86 strains, but not in O157 strains. These results support the hypothesis that in the intestinal tract of a child, serotype O86-specific Stx2 phage is lysogenized into highly-colonizing (diffusely-adhering and IgA1 protease-producing) O86 E.coli strains, resulting in the emergence of new EHEC, causing fatal HUS. It was also concluded that type III secretion is not essential for the development of HUS. Moreover, it is considered that Shiga toxin induces inflammatory cytokines such as IL-6 and IL-8 to cause HUS. We demonstrated that a Chinese herb, anisodamine, and an antimicrobial agent, azityhromycin, inhibited such an inflammatory cytokine induction, most probably blocking the NF-kB activation pathway.

儿童和老年人感染肠出血性大肠杆菌（EHEC）可导致溶血性尿毒症综合征（HUS），这是一种预后不良的严重并发症。肠出血性大肠杆菌的III型分泌系统（肠道定植机制）被认为对溶血性尿毒症的发展至关重要。然而，由于O86型肠出血性大肠杆菌引起的肠内感染，虽然大肠杆菌菌株没有III型分泌系统，但感染的儿童发生溶血性尿毒综合征而死亡。在这项研究中，我们研究了血清型O86肠出血性大肠杆菌菌株的分子遗传特性。这些菌株具有编码弥散粘附因子（HdaA）的120.73 kb质粒（pO86A）和编码2型志贺毒素（Stx2）的60.238 kb噬菌体。pO86A还具有福氏志贺氏菌IgA1蛋白酶基因，并对血清型O86肠出血性大肠杆菌菌株具有黏膜免疫抗性。Stx噬菌体具有O86菌株所具有的插入位点特性，而O157菌株没有。这些结果支持了一种假设，即在儿童肠道中，血清型O86特异性Stx2噬菌体被溶原为高度定植（弥漫性粘附和产生IgA1蛋白酶）的O86大肠杆菌菌株，导致新的肠出血性大肠杆菌的出现，导致致命的溶血性尿毒综合征。我们还得出结论，III型分泌物对溶血性尿毒综合征的发展并不是必需的。此外，志贺毒素诱导IL-6、IL-8等炎性细胞因子引起溶血性尿毒。我们证明了中药山莨菪碱和抗菌剂阿奇霉素抑制了这种炎症细胞因子的诱导，很可能阻断了NF-kB的激活途径。

项目成果

Colonization Behavior of the Virulent Genotypes of Helicobacter pylori, a Bacterial Risk Factor for Gastric Cancer, in the Human Gastric Mucosa : a Case Study from an Intrafamilial Infection

幽门螺杆菌（胃癌的细菌危险因素）的毒力基因型在人类胃粘膜中的定植行为：家庭内感染的案例研究

• 发表时间: 2004
• 期刊: Far Eastern International Pacific Medical Journal(Russia) 2
• 作者: Iwaya A;Nakagawa S;Iwakura N;Taneike I;Kurihara M;Kuwano T;Gondaira F;Endo M;Hatakeyama K;Yamamoto T;S.Nakagawa;S.Nakagawa;K.Kushiya;I.Taneike
• 通讯作者: I.Taneike

Rapid and quantitative detection of blood Serratia marccscens by a real-time PCR assay: its clinical application and evaluation in a mouse infection model.

通过实时 PCR 测定快速定量检测血液粘质沙雷氏菌：其在小鼠​​感染模型中的临床应用和评估。

• 发表时间: 2005
• 期刊: FEMS Microbiol. Lett. 248(2)
• 作者: Iwaya A;Nakagawa S;Iwakura N;Taneike I;Kurihara M;Kuwano T;Gondaira F;Endo M;Hatakeyama K;Yamamoto T
• 通讯作者: Yamamoto T

A Panton-Valentine leukocidin (PVL)-positive community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strain, another such strain carrying a multiple-drug resistance plasmid, and other more-typical PVL-negative strains found in Japan.

潘顿瓦伦丁杀白细胞素 (PVL) 阳性社区获得性耐甲氧西林金黄色葡萄球菌 (MRSA) 菌株、另一种携带多重耐药质粒的菌株，以及在日本发现的其他更典型的 PVL 阴性菌株。

• 发表时间: 2005
• 期刊: J. Clin. Microbiol 43(7)
• 作者: Takizawa Y;Taneike I;Nakagawa S;Oishi T;Nitahara Y;Iwakura N;Ozaki K;Takano M;Nakayama T;Yamamoto T
• 通讯作者: Yamamoto T

Intrafamilial Spread of the Same Clarithromycin-Resistant Helicobacter pylori Infection Confirmed by Molecular Analysis

分子分析证实同一克拉霉素耐药幽门螺杆菌感染在家庭内传播

• 发表时间: 2004
• 期刊: Journal of Clinical Microbiology 42
• 作者: Iwaya A;Nakagawa S;Iwakura N;Taneike I;Kurihara M;Kuwano T;Gondaira F;Endo M;Hatakeyama K;Yamamoto T;S.Nakagawa;S.Nakagawa;K.Kushiya;I.Taneike;I.Taneike
• 通讯作者: I.Taneike

日露学術交流Handbook

日俄学术交流手册

• 发表时间: 2005
• 作者: Iwaya A;Nakagawa S;Iwakura N;Taneike I;Kurihara M;Kuwano T;Gondaira F;Endo M;Hatakeyama K;Yamamoto T;S.Nakagawa;S.Nakagawa;K.Kushiya;I.Taneike;I.Taneike;T.Yamamoto;山本 達男
• 通讯作者: 山本 達男