Microbiome and Early Development of Mucosal Immune System

微生物组和粘膜免疫系统的早期发育

• 批准号: RGPIN-2019-04553
• 负责人: Griebel, Philip
• 金额: $ 2.91万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714555
• 关键词: Microbiome; Early; Development; Mucosal; Immune

A connection between the regulation of inflammatory responses in the lung and regulatory T cells (Tregs) is well established for mice and humans and there is increasing evidence that the microbiome plays an important role in the induction of Treg cells throughout the small intestine. My research in young calves demonstrated microbial colonization of the intestine begins during birth and this colonization is associated with extensive developmental changes in the mucosal immune system. It is not known, however, whether this early microbial colonization is associated with an induction of Tregs in the bovine intestine. Further, it is not known whether Tregs induced in the bovine intestine can home to the lung and play a role in regulating inflammatory responses following pulmonary invasion by bacterial pathogens that colonize the upper respiratory tract (URT). My research program will focus on the role of the microbiome in the induction of Tregs in the small intestine of newborn calves. We will characterize Treg populations throughout the intestine of newborn calves and correlate their development with regional microbiome analyses to determine if the presence of commensal bacteria is significantly associated with Treg development. These analyses will focus on a detailed phenotypic and functional characterization of all potential enteric Treg subpopulations and identify specific populations responding to the microbiome. A second objective is to determine whether enteric exposure of newborn calves to commensal bacteria that reside in the URT can also induce enteric antigen-specific Tregs. We will analyze Treg responses to two bacteria, Mannheimia haemolytica (Mh) and Pasteurella multocida (Pm) that are both commensals in the URT and major bovine respiratory pathogens. Our preliminary data indicate oral ingestion of these bacteria during the first week of life reduces inflammatory responses in the bovine lung. Therefore, we will determine if oral immunization of newborn calves with these two bacteria increases the abundance of antigen-specific Tregs in the lung and analyze the mechanisms by which these Tregs suppress inflammatory responses. Experimental respiratory challenges with Mh and Pm will also be used to determine if suppressed lung inflammation is associated with enhanced bacterial clearance and control of lung pathology. These studies will be of broad significance in understanding relationships between commensal bacteria in both the intestine and URT and how neonatal exposure to these bacteria influences development of immune responses. Further, if enteric exposure to URT commensal bacteria induces Tregs homing to the lung this will reveal a novel oral vaccine strategy for the control of respiratory disease when URT commensal bacteria invade the lung. This information will be of broad significance for vaccine development since URT commensal bacteria are known to be opportunistic invaders of the lung in humans and many domestic species.

在小鼠和人类中，肺中炎症反应的调节与调节性T细胞（Treg）之间的联系已经建立，并且越来越多的证据表明微生物组在整个小肠中诱导Treg细胞方面起着重要作用。我在年轻小牛中的研究表明，肠道的微生物定植始于出生期间，这种定植与粘膜免疫系统的广泛发育变化有关。然而，目前尚不清楚这种早期微生物定植是否与牛肠道中的TcB诱导有关。此外，尚不清楚在牛肠中诱导的TcB是否可以归巢至肺，并在上呼吸道（URT）定植的细菌病原体侵入肺后调节炎症反应中发挥作用。我的研究计划将集中在微生物组在新生小牛小肠中诱导THBE的作用。我们将表征新生小牛整个肠道中的Treg群体，并将其发育与区域微生物组分析相关联，以确定肠道细菌的存在是否与Treg发育显著相关。这些分析将侧重于所有潜在肠道Treg亚群的详细表型和功能表征，并鉴定对微生物组有反应的特定群体。第二个目的是确定新生小牛肠道暴露于URT中的肠道细菌是否也能诱导肠道抗原特异性TcB。我们将分析Treg对两种细菌的反应，溶血性曼氏菌（Mh）和多杀性巴氏杆菌（Pm），这两种细菌都是URT和主要牛呼吸道病原体中的寄生虫。我们的初步数据表明，在出生后的第一周内口服这些细菌可以减少牛肺的炎症反应。因此，我们将确定用这两种细菌口服免疫新生小牛是否增加了肺中抗原特异性Tcls的丰度，并分析这些Tcls抑制炎症反应的机制。还将使用Mh和Pm的实验性呼吸挑战来确定抑制的肺部炎症是否与增强的细菌清除和肺部病理控制相关。这些研究将在了解肠道和URT中的肠道细菌之间的关系以及新生儿暴露于这些细菌如何影响免疫反应的发展方面具有广泛的意义。此外，如果肠道暴露于URT肠道细菌诱导T细胞归巢至肺，则这将揭示当URT肠道细菌侵入肺时用于控制呼吸系统疾病的新型口服疫苗策略。这一信息将对疫苗开发具有广泛意义，因为已知URT肺细菌是人类和许多家养物种肺的机会性入侵者。