Understanding bacterial resistance to therapeutic phage cocktails in an animal model of infection

这项研究是针对噬菌体（噬菌体），一种专门感染和杀死细菌细胞的病毒，使噬菌体疗法成为治疗细菌感染的令人兴奋的选择。随着抗生素耐药性的威胁日益严重，在噬菌体治疗方面有相当大的商业和学术投资，但其在人类和动物中的成功应用仍然存在障碍。虽然在了解细菌如何在实验室条件下抵抗噬菌体捕食方面取得了令人难以置信的进展，但这些过程在实际感染中的重要性尚不清楚。这些知识对于选择治疗鸡尾酒中的噬菌体至关重要，这些鸡尾酒可以共同对抗这些细菌防御系统。我们研究大肠杆菌的发病机制已有20多年，了解特定菌株如何引起不同类型的感染，我们现在将这些知识应用于噬菌体治疗的开发，这需要研究噬菌体在感染过程中与宿主中目标细菌的相互作用。这项研究的主要重点将是全球传播的多重耐药大肠杆菌ST 131如何在感染哺乳动物膀胱时抵抗噬菌体治疗，这项工作将建立在三年的实验室数据基础上，包括人工尿液中的相互作用。该项目的一个关键方面将是应用猪尿路感染模型，其中可以研究噬菌体捕食和细菌耐药性的动态。博士学位的50%由Proteon制药公司资助，他们为研究带来了丰富的噬菌体治疗开发专业知识。我们预计这项研究将涉及噬菌体捕食后恢复的细菌群体的表达和序列分析，其中心主题是需要了解宿主感染期间细菌群体的异质性，以选择最有效的噬菌体组合。这项工作将与其他受资助的研究一起进行，研究噬菌体干预狗的尿路感染和牛胃肠道中的大肠杆菌O157。该项目将受益于校园内世界级的设施，包括大型动物研究和成像设施（LARIF），以及Proteon制药公司提供的知识和资源，该公司拥有开发和商业化用于动物和人类健康的噬菌体产品的平台。

The research is on bacteriophage (phage), viruses that specifically infect and kill bacterial cells, making phage therapy an exciting option to treat bacterial infections. With the growing threat of antibiotic resistance, there is considerable commercial and academic investment in phage therapy but hurdles still exist to its successful application in both humans and animals. While there has been incredible progress in understanding how bacteria resist phage predation under laboratory conditions, the importance of these processes during actual infections is unknown. This knowledge is critical to selection of phage in therapeutic cocktails that can work together to counter these bacterial defence systems. Our grouping has worked on the pathogenesis of Escherichia coli for over twenty years, understanding how specific strains cause different types of infection and we are now applying this knowledge to development of phage therapy which requires studying the interaction of phage with their target bacteria in the host during infection. The major focus of the research will be how the globally disseminated multi-drug resistant E. coli ST 131 resists phage treatment while infecting the mammalian bladder, and the work will build on three years of laboratory data including interactions in artificial urine. A key aspect of the project will be the application of a pig model of urinary tract infection in which the dynamics of phage predation and bacterial resistance can be studied. The PhD is 50% funded by Proteon Pharmaceuticals and they bring a wealth of expertise in phage therapy development to the research. We anticipate that the research will involve expression and sequence analysis of bacterial populations recovering from phage predation with a central theme of needing to understand bacterial population heterogeneity in the host during infection to select the most effective phage combinations. This work will run alongside other funded research developing phage interventions for UTI infections in dogs and E. coli O157 in the gastrointestinal tract of cattle. This project will benefit from world class facilities on campus including the Large Animal Research and Imaging Facility (LARIF) and the knowledge and resources provided by Proteon Pharmaceuticals, which has a platform to develop and commercialize phage-based products for animal and human health.