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Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence
Gut ( IF 24.5 ) Pub Date : 2017-08-08 , DOI: 10.1136/gutjnl-2017-314195
Bruno Lamas , Marie-Laure Michel , Nadine Waldschmitt , Hang-Phuong Pham , Vassiliki Zacharioudaki , Louise Dupraz , Myriam Delacre , Jane M Natividad , Gregory Da Costa , Julien Planchais , Bruno Sovran , Chantal Bridonneau , Adrien Six , Philippe Langella , Mathias L Richard , Mathias Chamaillard , Harry Sokol

Objective In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9 –/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli. Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms. Design C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9 –/– mice. To explore the impact of Card9 –/–microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9 –/– (Card9–/– →GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis. Results CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium-induced colitis was observed in Card9–/– →GF mice. The microbiota of Card9 –/– mice failed to outcompete the monosaccharide-consuming C. rodentium, worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9 –/– mice. Conclusions CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.

中文翻译:

Card9 通过微生物群调节和细菌毒力控制介导对肠道病原体的易感性

目的与先天免疫和适应性免疫相关,微生物群控制对肠道病原体的定植抗性。Caspase 募集域 9 (CARD9) 是一种关键的先天免疫基因,是塑造正常肠道微生物群所必需的。Card9 –/– 小鼠更容易受到肠道小鼠病原体柠檬酸杆菌啮齿动物的影响,该病原体模仿人类感染肠病原性和肠出血性大肠杆菌。在这里,我们研究了 CARD9 如何通过依赖微生物群和不依赖微生物群的机制控制 C.rodentium 感染易感性。在常规和无菌 (GF) 野生型 (WT) 和 Card9 –/– 小鼠中评估了设计 C.rodentium 感染。为了探索 Card9 –/– 微生物群对感染易感性的影响,GF WT 小鼠在 C. 啮齿动物感染。通过 16S rDNA 基因测序确定微生物群组成。炎症严重程度由组织学评分和脂质运载蛋白水平确定。通过定量 PCR 分析评估微生物群 - 宿主免疫系统的相互作用。结果 CARD9 通过支持特定的体液反应以与微生物群无关的方式控制病原体毒力。在 Card9–/– →GF 小鼠中观察到对 C.rodentium 诱导的结肠炎的更高易感性。Card9 –/– 小鼠的微生物群未能与消耗单糖的 C.rodentium 竞争,从而加剧了感染的严重程度。富含多糖的饮食抵消了 C.rodentium 的生态优势和 Card9 –/– 小鼠中病原体特异性抗体反应的缺陷。结论 CARD9通过以依赖微生物群和不依赖微生物群的方式控制病原体毒力来调节肠道感染的易感性。饮食干预可以恢复体液免疫和竞争性微生物群,从而克服对肠道病原体的遗传易感性。
更新日期:2017-08-08
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