The intestinal microenvironment must be carefully balanced to maintain a mutualistic relationship between host cells and commensal microbes while remaining non-permissive to undesirable pathogenic species. Enteric infection and intestinal disorders correspond to enhanced adaptive immune responses resulting from a breakdown in the normal avenues of host-microbe interactions. Identifying and understanding the means by which signals and antigen present in the intestinal lumen are accessed by host immune cells, and how these means are altered in a diseased state, has thus been a longstanding interest. Our preliminary data suggest that fibroblastic stromal cells located in small intestinal Peyer's patches form a network of collagen-rich reticular conduits which participate in the selective transport of small soluble molecules that have crossed the surface epithelium. Whether this novel avenue of molecular transport renders soluble signals or antigen more accessible to immune cells remains unclear.
The first aim of this proposed study will therefore address the possibility that the reticular conduit network of the intestinal Peyer's patc functions as an important, discriminatory avenue for delivery of small molecular weight molecules to the immune cell population of the PP follicle. To this end, we will carefully ascertain the types of molecules permitted within the conduit network and determine the extent to which immune cells resident in the PP are capable of acquiring the signals or antigen that flow through these structures. Interestingly, our preliminary findings also suggest that transport of molecules through these conduit networks require directional fluid flow provided by net water absorption across the epithelium - a process that is often disrupted under conditions of infectious and inflammatory disease. The controlled avenues by which immune cells encounter lumenal contents of the intestine and sense microbial populations likely determine the nature of host-microbe interactions.
The second aim of this study will therefore functionally test the possibility that the dependence of conduit-mediated transport on directional fluid flow may functionally limit this pathway under conditions of malabsorption and infectious diarrheal disease. We hypothesize that careful analysis of the extent to which peyer's patch conduits are utilized for intercellular transport of lumenal contents to immune cells, and the sensitivity of ths system to conditions of altered fluid absorption, will yield important insights to microbial sensin and mucosal immune responses.
The avenues by which immune cells sense and respond to the contents of the intestine are incredibly complex and poorly understood. Unraveling this complexity will be critically important for our understanding of the intestinal environment and ultimately the development of improved therapeutic strategies to intestinal infection and disease. The goal of this project is to investigate the role of a novel route of molecular transport to intestinal immune organs mediated by a collagen-rich network of conduits.
