Modeling the initial host immunopathologic response to Mycobacterium avium subspecies paratuberculosis infection in young cattle

Mycobacterium avium subspecies paratuberculosis (Map) is the causative agent of Johne\u27s disease, which is a chronic fatal granulomatous enteritis of ruminants throughout the world. The immunopathology during the initial host-pathogen interaction is incompletely understood. In this dissertation, we utilized a variety of bovine models in order to investigate the role of gamma/delta T lymphocyte subsets at initial Map infection sites in cattle. We are interested in how these early events may influence the subsequent immune response and ultimately disease outcome and progression. The subcutaneous infection model in young cattle was used to investigate the patterns of gamma/delta T cell subset recruitment to early Map infection sites, and how these cells may influence granuloma morphology during early infection. In the second project, we adapted the subcutaneous model using a biopolymer matrix which allowed for further phenotypic and functional characterization of immune cells including gamma/delta T cell subsets recruited to early Map infection sites. Our data suggests that bovine gamma/delta T cells have subset-specific roles during the initial anti-mycobacterial immune response, and that gamma/delta T cells may be central regulators of initial infection. Because the site of initial Map infection in cattle is considered to be the distal ileum, we next worked towards development of a novel bovine intestinal model which could be used to examine the role of gamma/delta T cells at the natural infection site (the distal ileum). By inoculation of live Map directly into ileo-cecal lymphoid tissue, we were able to demonstrate consistent intestinal colonization by Map. Further, this model allows for further investigation of the local and systemic immunologic responses during early intestinal Map infection. In summary, these models are useful for working towards further elucidation of the pathogenesis and immunopathology of Map infection in cattle, particularly during the early and subclinical infection periods