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Investigating phage therapy for the treatment of urinary tract infections

研究噬菌体疗法治疗尿路感染

基本信息

批准号：
10677257
负责人：
Jacob Jeffrey Zulk
金额：
$ 4.77万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2025-08-08
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677257
关键词：
Affect Animal Model Antibacterial Response Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Attenuated Automobile Driving Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacteriology Bacteriophages Binding Bladder Campylobacter coli Cells Clinic Clinical Collection Communities Complement Data Defect Development Diabetes Mellitus Diagnosis Disease model Elderly Environment Enzyme-Linked Immunosorbent Assay Epithelium Escherichia coli Fellowship Flow Cytometry Goals Growth Health Care Costs Human Immune Immune response Impairment In Vitro Infection Intracellular Space Knowledge Label Lipopolysaccharides Mammalian Cell Medical Medicine Membrane Membrane Proteins Mentorship Methods Microscopy Modeling Mus Mutation Nutrient Nutrient availability Organoids Pathogenesis Patients Phage Receptors Predisposition Proteins Public Health Publishing Recurrence Research Research Personnel Resistance Route Safety Techniques Testing Therapeutic Training Translating United States Urinary tract Urinary tract infection Urine Uropathogenic E. coli Virus Western Blotting Woman Work antimicrobial antimicrobial peptide bacterial fitness career career development college cost cytokine driving force environmental stressor experience extracellular fitness host microbiome human imaging in vivo in vivo Model infectious disease treatment innovation live cell imaging mouse model mutant novel pathogen pathogenic bacteria receptor recurrent infection skills standard of care superresolution microscopy tool uptake urinary

项目摘要

Urinary tract infections (UTIs) are responsible for a large public health burden with over half of women experiencing a UTI during their lifetime. These infections, primarily in women, older adults, and those with underlying conditions such as diabetes, are responsible for over $3.5 billion in health care costs annually in the USA alone. The majority of UTIs are caused by uropathogenic E. coli (UPEC) and are readily treated with antibiotics. However, global rise of antibiotic resistance amongst bacterial pathogens threatens the utility of the current standard of care. Furthermore, up to 30% of UPEC UTIs will have recurrence within 6 months of treatment due to intracellular UPEC reservoirs that are hidden from antibiotic therapy. Because of these reasons, alternatives to antibiotics are desperately needed. Bacteriophages (phage), viruses that infect bacteria, have long been hypothesized as a treatment for bacterial infection, predating the use of antibiotics by over a quarter of a century. Unfortunately, like antibiotics, bacteria can become resistant to phage. Preliminary work has identified several phage-resistant UPEC harboring mutations in lipopolysaccharide (LPS). These bacteria, although capable of evading phage, are poorer at growing in urine and at colonizing the bladder than their parental strains. The exact reason(s) for these fitness defects, however, are unknown. This work also aims to assess the utility of phage for treating intracellular UPEC reservoirs, which are untouched by antibiotic therapy, and which lead to UTI recurrence. Published and preliminary data suggests phage can interact and be internalized by bladder cells, although no group has tested the ability of phage to reduce intracellular UPEC burdens. Taken together, this preliminary data supports the hypothesis that phage therapy, through driving phage resistance that leaves bacteria less fit, and through phage interactions with the bladder, will be effective at treating both intracellular and extracellular UTIs. This hypothesis will be investigated by the following specific aims: 1) Identify mechanisms underlying decreased growth in urine and poor colonization of the murine bladder in phage resistant (LPS mutant) UPEC, 2) Characterize phage binding and internalization by the uroepithelium, reduction of intracellular reservoirs, and stimulation of bladder immune responses. In investigating these aims, several innovative tools such as primary bladder cell-derived organoids, super-resolution microscopy, and in vivo mouse models of disease and phage therapy will be used. This proposal will provide the candidate with training in UTI animal models, advanced microscopy techniques, protein isolation, and bladder organoid models. This training, along with excellent mentorship and career development goals, will provide the candidate with the necessary skills for an independent research career studying novel translational treatments for infectious disease. This training will take place at Baylor College of Medicine under the mentorship of leaders in the fields of antimicrobial resistance, phage therapy, and host-pathogen interactions. Taken together, this research will provide the information necessary to translate UTI phage therapy from the bench into the clinic.

尿路感染（UTI）是一个巨大的公共卫生负担，超过一半的妇女在他们的一生中经历UTI。这些感染，主要发生在妇女、老年人和糖尿病等基础疾病每年造成超过35亿美元的医疗保健费用，美国独自。大多数尿路感染是由尿路致病性大肠杆菌引起。大肠杆菌（UPEC），并易于用抗生素然而，细菌病原体中抗生素耐药性的全球上升威胁到抗生素的效用。目前的护理标准。此外，高达30%的UPEC UTI将在治疗后6个月内复发由于细胞内UPEC储库隐藏在抗生素治疗之外。由于这些原因，迫切需要抗生素的替代品。噬菌体，感染细菌的病毒，长期以来一直被假设为治疗细菌感染，比抗生素的使用早了四分之一以上。一个世纪。不幸的是，像抗生素一样，细菌也会对噬菌体产生抗药性。前期工作已鉴定了几种携带脂多糖（LPS）突变的抗噬菌体UPEC。这些细菌，虽然能够逃避噬菌体，但在尿中生长和在膀胱中定植方面比它们差。亲本品系然而，这些适应性缺陷的确切原因尚不清楚。这项工作还旨在评估噬菌体用于治疗细胞内UPEC储库的效用，其未被抗生素治疗触及，导致尿路感染复发。已发表的和初步的数据表明，噬菌体可以相互作用，尽管没有研究小组测试过噬菌体减少细胞内UPEC的能力，负担综上所述，这一初步数据支持了噬菌体疗法通过驱动通过噬菌体与膀胱的相互作用，使细菌不太适合的噬菌体抗性将是有效的在治疗细胞内和细胞外UTI方面。这一假设将通过以下具体的研究进行调查目的：1）确定尿液中生长减少和小鼠膀胱定植不良的潜在机制在噬菌体抗性（LPS突变体）UPEC中，2）表征噬菌体结合和被尿上皮内化，减少细胞内储库和刺激膀胱免疫应答。在研究这些目标时，几种创新工具，如原代膀胱细胞衍生的类器官，超分辨率显微镜，和体内将使用疾病和噬菌体治疗的小鼠模型。本建议书将为候选人提供培训在UTI动物模型、先进的显微镜技术、蛋白质分离和膀胱类器官模型中。这培训，沿着优秀的指导和职业发展目标，将为候选人提供独立研究职业的必要技能，研究感染性疾病的新型转化治疗疾病这项培训将在贝勒医学院进行，由该领域的领导人指导。抗菌素耐药性、噬菌体治疗和宿主-病原体相互作用。总的来说，这项研究将提供了将UTI噬菌体疗法从实验室转化为临床所需的信息。