Grant: Discovery Grants Program - Individual

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.