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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：
10357959
负责人：
June Louise Round
金额：
$ 62.75万
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357959
关键词：
Abdominal Pain 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 Goals Health Homeostasis Human Immune Immune response Immune system Immunity Immunologist Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inoviridae Malnutrition Mediating Microbe Modeling Multi-Drug Resistance Mus Myoviridae Pathogenesis Pattern recognition receptor Persons Physiological Play Population Probiotics Production Prophages Receptor Activation Role Route Safety Science Scientist Serum Severities Siphoviridae Stimulus TLR3 gene Tail Testing Therapeutic Intervention Time Ulcerative Colitis Vaccinated Vaccination Vaccines Virulence Virus Work Wound Infection base cell type cytokine defined contribution fecal transplantation gastrointestinal gut inflammation gut microbiome gut microbiota microbial 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.

炎症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人的炎症性肠病（IBD）的类型。全世界的人。IBD的特征是慢性进行性肠道炎症，很大程度上是由于易感个体的肠道微生物组被破坏。病原体感染，如粘附性侵袭性大肠杆菌（AIEC）尤其加剧IBD发病机制。恢复的治疗策略肠道微生物群稳态如益生菌和粪便微生物群移植显示出治疗IBD的前景。然而，这些治疗策略主要集中在微生物群的细菌成分上。最肠道中丰富的实体是感染这些细菌的噬菌体（噬菌体）。即使它是虽然我们认识到噬菌体群体在IBD恶化期间扩张，但我们对如何扩张知之甚少，炎症因子参与IBD的发病机制。我们最近的工作表明，不同种类的植物由人和鼠免疫细胞上的模式识别受体识别。我们发现丝状真菌触发TLR3依赖性炎症反应，促进伤口感染模型中的细菌感染。针对这些细菌接种疫苗是预防伤口感染的有效策略。我们还发现尾状尾病毒目刺激肠道中的TLR9依赖性炎症。根据这些观察，我们推测粘附侵袭性E.大肠杆菌调节免疫反应的方式，加重IBD。为了验证这一假设，我们建立了一个由微生物学家、免疫学家和疫苗科学家在目标1中，我们将描述炎症条件如何刺激噬菌体复制在肚子里。在目标2中，我们将确定先天模式识别对噬菌体的识别范围受体。在目标3中，我们将开发和优化治疗IBD的抗噬菌体疫苗策略。我们一起努力，这些目标代表了一种新的和及时的方法，不仅可以了解炎症是如何影响IBD的，致病机制，但用于评估噬菌体疗法治疗多重耐药细菌的安全性和有效性感染.