Bacteriophage pathobiology of inflammatory bowel disease

炎症性肠病的噬菌体病理学

基本信息

批准号：
10601011
负责人：
June Louise Round
金额：
$ 61.28万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-06 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601011
关键词：
Abdominal Pain Adherent Invasive Escherichia coli Adjuvant Affect Antibody titer measurement Antigens Antiviral Response Bacteria Bacterial Infections Bacteriophages Biological Assay Caudovirales Cells Cellular Immunity Chronic Coliphages Colitis Crohn&apos s disease Diarrhea Disease Engineering Escherichia coli Family Fatigue Fever Germ-Free Goals Health Homeostasis Human Immune Immune response Immune system Immunity Immunologic Stimulation Immunologist Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inoviridae Malnutrition Mediating Microbe Modeling Multi-Drug Resistance Mus Myoviridae Pathogenesis Pattern Recognition Pattern recognition receptor Persons Physiological Play Population Predisposition Probiotics Production Prophages Receptor Activation Role Route Safety Science Scientist Serum Severities Siphoviridae Stimulus TLR3 gene Tail Testing Therapeutic Intervention Ulcerative Colitis Vaccinated Vaccination Vaccines Virulence Virus Work Wound Infection cell type cytokine defined contribution fecal transplantation gastrointestinal gut inflammation gut microbiome gut microbiota immunoregulation microbial products microbiota mouse model murine colitis novel novel therapeutic intervention pathogen prevent prophylactic treatment strategy vaccine strategy

项目摘要

Bacteriophage pathobiology of inflammatory bowel disease Ulcerative colitis and Crohn’s disease are types of inflammatory bowels diseases (IBD) that affect millions of people around the world. IBD is characterized by chronic progressive intestinal inflammation which is driven in large part by disruption of the gut microbiome in susceptible individuals. Infection by pathogens such as adherent invasive Escherichia coli (AIEC) in particular exacerbates IBD pathogenesis. Treatment strategies that restore gut microbiota homeostasis such as probiotics and fecal microbiota transplantation show promise in treating IBD. These treatment strategies, however, focus primarily on the bacterial component of the microbiota. The most abundant entities in the gut are the bacteriophages (phages) that infect these bacteria. Even though it is recognized that phage populations expand during IBD exacerbations, we know surprisingly little about how phages contribute to IBD pathogenesis. Our recent work demonstrates that diverse species of phages are recognized by pattern recognition receptors on human and murine immune cells. We find filamentous phages trigger TLR3-dependent inflammatory responses that promote bacterial infection in a wound infection model. Vaccinating against these phages was an effective strategy at preventing wound infection. We also find that tailed Caudovirales phages stimulate TLR9-dependent inflammation in the gut. Based on these observations, we hypothesize that phages produced by adherent invasive E. coli modulate immune responses in ways that exacerbate IBD. To test this hypothesis, we have established a team of microbiologists, immunologists, and vaccine scientists. In Aim 1, we will characterize how inflammatory conditions stimulate bacteriophage replication in the gut. In Aim 2, we will determine how broadly bacteriophages are recognized by innate pattern recognition receptors. In Aim 3, we will develop and optimize an anti-bacteriophage vaccine strategy to treat IBD. Together, these aims represent a novel and timely approach in understanding not only how phages affect IBD pathogenesis, but for evaluating the safety and efficacy of phage therapy to treat multidrug-resistant bacterial infections.

炎性肠病的噬菌体病理生物学溃疡性结肠炎和克罗恩病是影响数百万的炎症类疾病（IBD）的类型世界各地的人。大部分是在感知个体中的肠道微生物组中断。侵入性大肠杆菌（AIEC）特别加剧了IBD发病机理。肠道菌群稳态，例如益生菌和粪便肥大菌群移植，在治疗IBD方面有希望。但是，这些治疗策略主要集中在微生物群的细菌成分上。肠道中的大量实体是感染这些细菌的双脚病（噬菌体）。认识到噬菌体种群在IBD加剧期间扩大，我们对如何如何如何了解噬菌体有助于IBD发病机理。通过人类和鼠免疫细胞上的模式识别受体识别。触发TLR3依赖性炎症反应，在伤口感染模型中促进细菌感染。针对噬菌体接种疫苗是预防伤口感染的有效策略。尾caudovirales噬菌体刺激肠道中的TLR9依赖性炎症。我们假设由辅助侵入性大肠杆菌模块化免疫反应产生的噬菌体以加剧了IBD。疫苗科学家在AIM 1中，我们将表征炎症条件在肠道中。受体。这些目的压抑了一种新颖而及时的方法，不仅要理解噬菌体如何影响IBD 发病机理，但用于评估噬菌体治疗多药耐药细菌的安全性和功效。感染。