Date of Award
Doctor of Philosophy
Our primary goal was to understand how a subclinical intestinal infection with Mycobacterium avium ss paratuberculosis (Map) would influence subsequent acute mucosal injury. To address this goal, we utilized a mouse model of intestinal Map infection. BALB/c mice were infected with Map strain K10 and subsequently administered a low dose of dextran sulfate sodium (DSS) in the drinking water to induce mild intestinal injury. Our central hypothesis was that persistent intestinal mycobacterial infection sensitizes the host to enhanced intestinal injury. In our first set of studies we demonstrated that subclinical and chronic intestinal mycobacterial infection amplifies acute mucosal injury. This was demonstrated by increased weight loss, increased frequency of rectal blood, and exacerbation of gross and histologic cecal lesions in mice infected with Map and treated with DSS. In the next group of experiments we set out to define the local intestinal and systemic immune responses that were associated with sensitivity of Map-infected mice to DSS. An additional aim was to confirm that Map infected mice had an antigen-specific immune response. We confirmed that Map infected mice had antigen-specific production of adaptive immune cytokines, namely, IFN-gamma; and IL-17, in addition to the production of Map-specific IgG2a and IgG1 antibody. Moreover, we observed enhanced activation of the innate rather than adaptive immune response in Map infected BALB/c mice treated with DSS. An innate mechanism was supported by infecting SCID mice with Map followed by DSS treatment, which resulted in similar clinical disease and mucosal pathology. A common feature of the disease in both BALB/c and SCID mice was increased expression of IL-1 beta;. In our last set of studies, we wanted to understand how Map infection, in the context of acute mucosal injury, promotes an augmented innate immune profile. Because Map infection was limited to mucosal macrophages, we focused our studies on intestinal macrophages. Our results from these studies suggested that Map infection promotes a basal level of IL-1 beta; and iNOS expression, thereby priming macrophage for enhanced IL-1 beta; secretion and increased iNOS expression following interaction with a second stimulus, namely, the commensal flora or LPS. The results from this thesis support the central hypothesis and suggest that Map enhanced activation of the innate immune response can sensitize the mucosa to DSS mediated inflammation.
Charles Scott Johnson
Johnson, Charles Scott, "Persistent enteric mycobacterial infection sensitizes mice to intestinal epithelial injury" (2010). Graduate Theses and Dissertations. 11339.