Recombinant bacteria expressing oligosaccharide receptor mimics for prevention of enteric infections

每年有300多万人死于胃肠道传染病。已知导致这些感染的主要微生物病原体利用宿主细胞表面的低聚糖作为粘胶蛋白或毒素的受体。我们已经开发了一种新的抗感染策略（并申请了专利），该策略基于对肠道病原体在无害载体细菌表面产生的毒素和粘附素的寡糖受体的模仿。口服这种重组益生菌具有通过结合和中和肠道内毒素以及通过阻断病原体粘附于肠上皮细胞来预防肠道感染的潜力。作为一个典型的例子，我们已经开发出一种能够预防志贺产毒大肠杆菌（STEC）感染的严重后果的细菌；该制剂结合志贺毒素的效率很高，在动物模型中具有100%的保护作用。然而，该策略具有非常广泛的应用，几乎任何病原体的受体都可以通过在合适的无害宿主细菌中表达适当的糖基转移酶来模拟。这项建议涉及扩大我们现有的工作，以开发治疗其他重要的危及生命的腹泻疾病的药物，包括霍乱、旅行者腹泻、痢疾、抗生素相关结肠炎、轮状病毒等。

Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant probiotics has the potential to prevent enteric infections by binding and neutralizing toxins in the gut lumen and by blocking adherence of the pathogen to intestinal epithelial cells. As a prototypic example, we have developed a bacterium capable of preventing the serious consequences of Shiga toxigenic Escherichia coli (STEC) infections; this agent binds Shiga toxin with very high efficiency and is 100% protective in animal models. The strategy has very broad applications, however, and receptors for virtually any pathogen can be mimicked by expression of appropriate glycosyl transferases in a suitable harmless host bacterium. This proposal involves extension of our existing work to develop therapeutic agents for other important life threatening diarrhoeal diseases including cholera, travellers' diarrhoea, dysentery, antibiotic-associated colitis, rotavirus, etc.