The regulation of the intestinal epithelium and host-pathogen interactions by the constitutive androstane receptor

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Johne’s disease, a wasting condition in ruminants, is caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP), which is transmitted via contaminated milk and through the fecal-oral route. Since signs and symptoms of Johne’s disease often take years to develop (during which MAP can be shed in the feces), it is difficult to implement traditional surveillance methods to reduce its spread. To limit the burden of infectious disease in livestock and natural ruminants we must understand the steps that lead to pathogen transmission, invasion and the host inflammatory response. Current efforts to understand key aspects of MAP invasion and infection are hindered by the use of experimental animal models that do not reflect important aspects of its natural transmission. In this grant, we propose to develop new experimental models to study the pathogenesis of Johne’s disease. In the first portion of our program, we will develop a model in mice that uses conditions that reflect the natural infection in ruminants. Since ruminants are infected via the oral route with low doses of MAP over extended periods of time, prior to developing Johne’s disease, we will use the same parameters to infect mice. In the second part of our program, we will develop a model that will allow us to assess aspects of MAP invasion into the host, by generating cultured “mini-guts” or “enteroids” from intestinal stem cells isolated from mice and cattle. These enteroids will allow us to visualize, in real-time, the entry of MAP into host cells following its micro-injection into the lumen. By developing these models, it will allow us to examine aspects of MAP entry and infection, in concert with the host’s response. The final aspect of our program will be to use our new models to examine the role that environmental stimuli play in regulating the host’s response to MAP. Since livestock and natural ruminants are exposed to a variety of compounds of environmental origin, we posit that these agents interact with specific receptors in the host, which ultimately affect its susceptibility to developing Johne’s disease. We anticipate that the new knowledge generated from our program will provide significant insight into the pathogenesis of Johne’s disease. The models that we will develop and validate will have broad-reaching impact, and could be used by investigators across Canada and beyond, to study MAP and evaluate the efficacy of new therapeutics to treat Johne’s disease in livestock and natural ruminants.