Synchronous Disease Kinetics in a Murine Model for Enterohemorrhagic E-coil Infection Using Food-Borne Inoculation
Synchronous Disease Kinetics in a Murine Model for Enterohemorrhagic E-coil Infection Using Food-Borne Inoculation
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DOI：
10.3389/fcimb.2016.00138
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发表时间：
2016-11-03
影响因子：
5.7
通讯作者：
Leong, John M.
中科院分区：
文献类型：
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作者：
Flowers, Laurice J.;Ghanem, Elsa N. Bou;Leong, John M.
在肠上皮定殖后，附着和消除（AE）病原体肠出血性大肠杆菌（EHEC）消除微绒毛并在粘附的细菌下方形成尿道样结构。其毒力因子之一，噬菌体编码的滋贺毒素（Stx）的产生导致全身性疾病，包括肾衰竭的发展。尽管EHEC不能有效感染常规小鼠，但可以利用天然鼠AE病原体啮齿柠檬酸杆菌（CR）的衍生物在小鼠中对EHEC感染进行建模。用CR（Phi Stx（2dact））、C.由编码在小鼠中具有高效力的Stx变体的噬菌体溶原化的啮齿目动物，特征在于肠上皮上的AE损伤形成和Stx介导的全身性疾病，包括肾损伤。该模型在某种程度上受到疾病过程中小鼠间差异的限制，至严重发病（和所需安乐死）的时间变化多达5天，这一特征限制了疾病定义阶段的病理学分析。在本研究中，我们改变并优化了CR（Phi Stx（2dact））的制备、剂量和递送方式，使用食源性感染途径来产生高度同步的疾病模型。我们发现，食源性接种低至3 × 10（4）CR（Phi Stx（2dact））导致生产性定殖和严重的全身性疾病。接种1 × 10（8）个细菌后，大多数感染动物在感染后5天开始体重减轻，所有动物均需要在第6天或第7天实施安乐死。这种增强的EHEC感染小鼠模型应有助于表征与Stx介导的疾病的特定阶段相关的病理学。
Upon colonization of the intestinal epithelium, the attaching and effacing (AE) pathogen Enterohemorrhagic Escherichia coil (EHEC) effaces microvilli and forms pedestal-like structures beneath the adherent bacterium. The production of one of its virulence factors, the phage-encoded Shiga toxin (Stx) results in systemic disease, including the development of renal failure. Although EHEC does not productively infect conventional mice, EHEC infection can be modeled in mice utilizing a derivative of the natural murine AE pathogen Citrobacter rodentium (CR). Gavage of mice with CR(Phi Stx(2dact)), a C. rodentiurn lysogenized by a phage encoding an Stx variant with high potency in mice, features AE lesion formation on intestinal epithelium and Stx-mediated systemic disease, including renal damage. This model is somewhat limited by mouse-to-mouse variation in the course of disease, with the time to severe morbidity (and required euthanasia) varying by as many as 5 days, a feature that limits pathological analysis at defined stages of disease. In the current study, we altered and optimized the preparation, dose, and mode of delivery of CR(Phi Stx(2dact)), using food-borne route of infection to generate highly synchronous disease model. We found that food borne inoculation of as few as 3 x 10(4) CR(Phi Stx(2dact)) resulted in productive colonization and severe systemic disease. Upon inoculation of 1 x 10(8) bacteria, the majority of infected animals suffered weight loss beginning 5 days post-infection and all required euthanasia on day 6 or 7. This enhanced murine model for EHEC infection should facilitate characterization of the pathology associated with specific phases of Stx-mediated disease.