The Mutant Mouse Resource and Research Center at the University of Missouri - Applied Research Section 1

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Applied Research section 1 – Project Summary After decades of efforts to rid laboratory mice of pathogens and other subclinical microbes capable of confounding research, there is an emerging realization that mice completely devoid of any and all viral, bacterial, protozoal, and fungal pathogens including even the most questionable opportunists, are essentially antigen-naïve and as such, may not serve as appropriate or ideal models of human disease. Several studies have demonstrated that pet store and wild mice are qualitatively different from standard laboratory mice in terms of circulating memory T cell and immunoglobulin profiles. This antigen-experienced immunophenotype is consistently associated with a protective effect in models of infectious disease, intestinal inflammation, and tumorigenesis, and this immunophenotype can be transferred experimental via the gut microbiota (GM). In the interests of biosecurity, worker safety, and reproducible data however, it would be ideal if the antigen- experienced immunophenotype could be induced in laboratory mice via experimental inoculation with the appropriate microbes. Thus, the long-term objectives of this Applied Research section are to investigate and develop methods of reproducibly inducing an antigen-experienced immunophenotype in laboratory mice which confers a protective effect in disease models previously shown to be sensitive to these factors. The Specific Aims are to 1) test the ability of two candidate bacterial ‘provocateurs’ of host immune responses, alongside a viral control and in the context of two distinct GM communities, to induce the differentiation of effector memory T cells and immunoglobulin production, and 2) to evaluate the susceptibility of mice in these experimental antigen exposure groups to disease susceptibility using two commonly used mouse models of disease known to differ in severity depending on the degree of previous host antigen exposure. Specifically, the microbial agents to be evaluated include Helicobacter hepaticus, segmented filamentous bacteria (Candidatus Savagella), and Murine Hepatitis Virus (MHV), and the models to be tested include Non-obese Diabetic (NOD) mice and DSS-induced colitis. If traditional laboratory mice used in translational biomedical research are universally more susceptible in disease models as suggested by recent studies, it essentially distorts our ability to identify mechanisms and therapies of disease, wasting time and resources on ‘false positives’ that do not translate to humans, and missing opportunities on ‘false negatives’ that show exaggerated toxicities that might not be present in antigen-experienced individuals. The development and refinement of methods such as those proposed in this Applied Research section will revolutionize biomedical research and increase efficiencies in the development of therapeutics and discovery of mechanisms. Moreover, generation and provision of mice with an antigen-experienced immunophenotype will expand the portfolio of services offered by the MU MMRRC related to the GM and its influence on mouse models of disease, and increase program income through novel value-added services applicable to a broad base of investigators.