Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa.
Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa.
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DOI：
10.1371/journal.ppat.1000902
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发表时间：
2010-05-13
期刊：
影响因子：
6.7
通讯作者：
Vallance BA
中科院分区：
文献类型：
--
作者：
Bergstrom KS;Kissoon-Singh V;Gibson DL;Ma C;Montero M;Sham HP;Ryz N;Huang T;Velcich A;Finlay BB;Chadee K;Vallance BA
尽管我们对附着性和消隐性（A/E）大肠杆菌感染的发病机制的理解最近取得了进展，但宿主防御这些微生物的机制尚不清楚。本研究的目的是确定杯状细胞来源的Muc2（主要的肠道分泌黏液蛋白和黏液层的主要成分）在宿主抵抗A/E病原体中的作用。为了评估Muc2在A/E细菌感染中的作用，我们给Muc2缺陷（Muc2−/−）小鼠接种了啮齿柠檬酸杆菌，这是一种与腹泻性A/E大肠杆菌相关的小鼠A/E病原体。与野生型（WT）小鼠不同，受感染的Muc2−/−小鼠表现出快速的体重减轻和高达90%的死亡率。在Muc2−/−小鼠中，粪便镀层显示出10-100倍的啮齿鼠负担，其中大部分被发现松散地粘附在结肠粘膜上。Muc2 - / -小鼠的组织学显示在局灶性细菌微菌落中结肠溃疡。大肠中分泌粘蛋白的代谢标记表明，与未感染的对照组相比，感染WT小鼠的粘蛋白分泌明显增加，这表明宿主利用增加的粘蛋白释放将病原体从粘膜表面冲洗掉。在感染过程中，Muc2也会影响宿主-共生菌的相互作用，因为FISH分析显示，C. rodentium微菌落含有大量的共生菌，而在WT小鼠中未观察到这一点。口服fitc -葡聚糖和FISH染色显示，与WT小鼠相比，Muc2−/−小鼠肠道屏障破坏明显加重，明显的病原体和共生易位进入Muc2−/−结肠粘膜。有趣的是，尽管结肠病理没有显著改变，但共生耗竭增强了Muc2−/−小鼠的C. rodentium定植。综上所述，Muc2的产生对A/E细菌感染期间的宿主保护至关重要，通过限制与结肠粘膜表面相关的总体病原体和共生体数量。这些作用限制了组织损伤和致病菌和共生菌在上皮上的易位。肠致病性大肠杆菌（EPEC）和肠出血性大肠杆菌（EHEC）是世界范围内腹泻疾病和其他严重并发症的重要原因。尽管许多研究解决了这些微生物使用的致病策略，但宿主如何保护自己免受这些病原体的侵害却知之甚少。我们在这里要解决的一个关键问题是，覆盖在肠道表面的厚黏液层是否在宿主保护中起作用。由于EPEC和EHEC不能有效地感染小鼠，我们使用了一种相关的小鼠病原体，称为鼠Citrobacter rodentium，来感染野生型小鼠和muc2缺陷小鼠，并比较它们的反应。我们发现，muc2缺陷小鼠极易受到啮齿c感染引起的死亡和疾病的影响。在整个实验过程中，muc2缺陷小鼠的定植速度更快，病原体负担也更高。在Muc2缺乏的小鼠中发现常驻（非致病性）细菌与C. rodentium和宿主组织相互作用，表明Muc2调节肠道表面所有形式的肠道微生物群。粘液分泌不足也导致肠道渗漏增加，从而使微生物进入粘膜组织。我们的研究表明，在EPEC/ ehec样病原体感染期间，muc2依赖性粘液的产生对于有效控制致病性和非致病性细菌至关重要。
Despite recent advances in our understanding of the pathogenesis of attaching and effacing (A/E) Escherichia coli infections, the mechanisms by which the host defends against these microbes are unclear. The goal of this study was to determine the role of goblet cell-derived Muc2, the major intestinal secretory mucin and primary component of the mucus layer, in host protection against A/E pathogens. To assess the role of Muc2 during A/E bacterial infections, we inoculated Muc2 deficient (Muc2−/−) mice with Citrobacter rodentium, a murine A/E pathogen related to diarrheagenic A/E E. coli. Unlike wildtype (WT) mice, infected Muc2−/− mice exhibited rapid weight loss and suffered up to 90% mortality. Stool plating demonstrated 10–100 fold greater C. rodentium burdens in Muc2−/− vs. WT mice, most of which were found to be loosely adherent to the colonic mucosa. Histology of Muc2−/− mice revealed ulceration in the colon amid focal bacterial microcolonies. Metabolic labeling of secreted mucins in the large intestine demonstrated that mucin secretion was markedly increased in WT mice during infection compared to uninfected controls, suggesting that the host uses increased mucin release to flush pathogens from the mucosal surface. Muc2 also impacted host-commensal interactions during infection, as FISH analysis revealed C. rodentium microcolonies contained numerous commensal microbes, which was not observed in WT mice. Orally administered FITC-Dextran and FISH staining showed significantly worsened intestinal barrier disruption in Muc2−/− vs. WT mice, with overt pathogen and commensal translocation into the Muc2−/− colonic mucosa. Interestingly, commensal depletion enhanced C. rodentium colonization of Muc2−/− mice, although colonic pathology was not significantly altered. In conclusion, Muc2 production is critical for host protection during A/E bacterial infections, by limiting overall pathogen and commensal numbers associated with the colonic mucosal surface. Such actions limit tissue damage and translocation of pathogenic and commensal bacteria across the epithelium. Enteropathogenic E. coli (EPEC) and Enterohemorrhagic E. coli (EHEC) are important causes of diarrheal disease and other serious complications worldwide. Despite many studies addressing the pathogenic strategies used by these microbes, how the host protects itself from these pathogens is poorly understood. A critical question we address here is whether the thick mucus layer that overlies the intestinal surface plays a role in host protection. Since EPEC and EHEC do not infect mice efficiently, we used a related mouse pathogen called Citrobacter rodentium to infect and compare responses between wildtype mice and Muc2-deficient mice, which are defective in mucus production. We show that Muc2-deficient mice are extremely susceptible to C. rodentium infection-induced mortality and disease. Muc2-deficient mice were also colonized faster and had higher pathogen burdens throughout the experiment. Resident (non-pathogenic) bacteria were found to interact with C. rodentium and host tissues in Muc2-deficient mice, indicating Muc2 regulates all forms of intestinal microbiota at the gut surface. Deficiency in mucus production also contributed to increased leakiness of the gut, which allowed microbes to enter mucosal tissues. Our study shows that Muc2-dependent mucus production is critical for effective management of both pathogenic and non-pathogenic bacteria during infection by an EPEC/EHEC-like pathogen.
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影响因子：
3.6
作者：
Chessa D;Winter MG;Jakomin M;Bäumler AJ
通讯作者：
Bäumler AJ
影响因子：
3.1
作者：
Bergstrom, Kirk S. B.;Guttman, Julian A.;Vallance, Bruce A.
通讯作者：
Vallance, Bruce A.
DOI：
10.1152/ajpgi.2001.280.5.g922
发表时间：
2001-05-01
影响因子：
4.5
作者：
Atuma, C;Strugala, V;Holm, L
通讯作者：
Holm, L
影响因子：
3.6
作者：
Deng, WY;Vallance, BA;Finlay, BB
通讯作者：
Finlay, BB
影响因子：
3.1
作者：
Barthel, M;Hapfelmeier, S;Hardt, WD
通讯作者：
Hardt, WD