NADPH oxidase deficient mice develop colitis and bacteremia upon infection with normally avirulent, TTSS-1- and TTSS-2-deficient Salmonella Typhimurium.
NADPH oxidase deficient mice develop colitis and bacteremia upon infection with normally avirulent, TTSS-1- and TTSS-2-deficient Salmonella Typhimurium.
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DOI：
10.1371/journal.pone.0077204
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hardt WD
中科院分区：
文献类型：
--
作者：
Felmy B;Songhet P;Slack EM;Müller AJ;Kremer M;Van Maele L;Cayet D;Heikenwalder M;Sirard JC;Hardt WD
感染、微生物采样和肠道微生物群及其产物偶尔泄漏穿过肠上皮细胞层代表了对肠免疫系统的永久性挑战。NADPH氧化酶产生活性氧被认为是防御的关键因素。患有慢性肉芽肿性疾病的患者缺乏NADPH氧化酶的亚基之一。它们表现出类似克罗恩病的肠道炎症的高发病率，并且对真菌和细菌感染极其敏感，包括患沙门氏菌病的风险增加10倍。目前还不完全清楚感染过程的哪些步骤受到NADPH氧化酶缺乏的影响。我们采用沙门氏菌腹泻的小鼠模型来研究NADPH氧化酶缺乏症（Cybb −/−）如何影响大肠粘膜的微生物处理。在该动物模型中，野生型S.鼠伤寒引起野生型小鼠明显的肠病。与此相反，无毒S.鼠伤寒沙门氏菌突变体（S.Tmavir; invGsseD），其缺乏促进跨上皮渗透和固有层生长的毒力因子，不能在野生型小鼠中引起肠病。我们发现Cybb −/−小鼠被S.Tmavir有效感染，并在感染后第4天发生肠病。Cybb −/− Myd 88 −/−小鼠的细胞耗竭实验和感染表明，Cybb −/−小鼠中S. Tmavir引起的疾病取决于CD 11 c + CX 3CR 1+单核吞噬细胞介导盲肠固有层的定植和Myd 88依赖性促炎免疫反应。有趣的是，在混合的骨髓嵌合体中，骨髓衍生区室中Cybb-熟练度的部分重建足以改善疾病的严重程度。我们的数据表明，NADPH氧化酶的表达是至关重要的限制生长的S.Tmavir在粘膜固有层。这提供了重要的见解微生物处理大肠粘膜和NADPH氧化酶的作用，在维持微生物-宿主互惠在这个暴露的身体表面。
Infections, microbe sampling and occasional leakage of commensal microbiota and their products across the intestinal epithelial cell layer represent a permanent challenge to the intestinal immune system. The production of reactive oxygen species by NADPH oxidase is thought to be a key element of defense. Patients suffering from chronic granulomatous disease are deficient in one of the subunits of NADPH oxidase. They display a high incidence of Crohn’s disease-like intestinal inflammation and are hyper-susceptible to infection with fungi and bacteria, including a 10-fold increased risk of Salmonellosis. It is not completely understood which steps of the infection process are affected by the NADPH oxidase deficiency. We employed a mouse model for Salmonella diarrhea to study how NADPH oxidase deficiency (Cybb −/−) affects microbe handling by the large intestinal mucosa. In this animal model, wild type S. Typhimurium causes pronounced enteropathy in wild type mice. In contrast, an avirulent S. Typhimurium mutant (S.Tmavir; invGsseD), which lacks virulence factors boosting trans-epithelial penetration and growth in the lamina propria, cannot cause enteropathy in wild type mice. We found that Cybb −/− mice are efficiently infected by S.Tmavir and develop enteropathy by day 4 post infection. Cell depletion experiments and infections in Cybb −/− Myd88 −/− mice indicated that the S.Tmavir-inflicted disease in Cybb −/− mice hinges on CD11c+CX3CR1+ monocytic phagocytes mediating colonization of the cecal lamina propria and on Myd88-dependent proinflammatory immune responses. Interestingly, in mixed bone marrow chimeras a partial reconstitution of Cybb-proficiency in the bone marrow derived compartment was sufficient to ameliorate disease severity. Our data indicate that NADPH oxidase expression is of key importance for restricting the growth of S.Tmavir in the mucosal lamina propria. This provides important insights into microbe handling by the large intestinal mucosa and the role of NADPH oxidase in maintaining microbe-host mutualism at this exposed body surface.
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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
3.1
作者：
Bispham, J;Tripathi, BN;Wallis, TS
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Wallis, TS
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
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Littman, DR
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3.1
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Conlan, JW
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Conlan, JW
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Coburn, B;Li, YL;Finlay, BB
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Finlay, BB