Bacteriophage pathobiology of inflammatory bowel disease

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炎症性肠病(IBD)的一种类型，影响数百万人 世界各地的人们。IBD的特征是慢性进行性肠炎，它是由 很大程度上是由于易感人群肠道微生物群的破坏所致。粘附性等病原体感染 侵袭性大肠杆菌(AIEC)尤其加重IBD的发病。恢复的治疗策略 肠道微生物区系动态平衡，如益生菌和粪便微生物区系移植，在治疗IBD方面显示出良好的前景。 然而，这些治疗策略主要集中在微生物区系的细菌成分上。最多的 肠道中丰富的物质是感染这些细菌的噬菌体。即使它是 认识到在IBD恶化期间噬菌体种群会扩张，我们对如何扩张知之甚少，令人惊讶 噬菌体参与了IBD的发病过程。我们最近的研究表明，不同种类的噬菌体 由人类和小鼠免疫细胞上的模式识别受体识别。我们发现丝状噬菌体 在伤口感染模型中，触发依赖TLR3的炎症反应，促进细菌感染。 接种这些噬菌体疫苗是预防伤口感染的有效策略。我们还发现， 尾状尾状病毒噬菌体刺激肠道中依赖TLR9的炎症。基于这些观察， 我们假设，粘附性侵袭性大肠杆菌产生的噬菌体通过以下方式调节免疫反应 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。 在肠子里。在目标2中，我们将确定通过先天模式识别识别噬菌体的范围有多广 感受器。在目标3中，我们将开发和优化抗噬菌体疫苗策略来治疗IBD。一起， 这些目标代表了一种新的和及时的方法，不仅理解噬菌体如何影响IBD 发病机制，但用于评价噬菌体疗法治疗多重耐药细菌的安全性和有效性 感染。

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.