FRAGILE ANIMAL MODELS OF HUMAN DISEASE

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Project 1: Use of Severe Combined Immunodeficient and Immunocompetent Mice to Analyze the Pathogenesis of Oral Listeriosis (and CNS-Disease) We propose to use Severe Combined Immunodeficient (scid) and Immunocompetent (imcomp) mice, either conventionally reared (CNV) or with no gut microbial flora (GF, germ free) as models to analyze the pathogenesis or oral infection by L. monocytogenes and the host response to such gut mucosal challenge. L. monocytogenes is an opportunistic, sometimes fatal, pathogen of humans and a more common pathogen of domestic food animals. We have developed the first laboratory animal model for Central Nervous System (CNS)-listeriosis following oral infection. Oral infection of CNV scid mice with 'wild-type' L. monocytogenes results in CNS-infection and symptoms--classically 'circling disease' and death within 14-21 days. We plan to use 'wild-type' virulent L. monocytogenes, and four virulence- factor negative ('knock-out') strains of L.monocytogenes to probe the mechanisms of pathogenesis via the gut mucosal route and the role the elements of the host's mucosal immune system may play to prevent, contain, and resolve gut mucosal infections. We believe our finds may be relevant to understanding and immunizing versus gut mucosal infections. We believe our findings may be relevant to understand and immunizing versus gut mucosal infections by many facultative, intracellular bacterial pathogens. We aim to: 1) analyze how oral/gut mucosal L. monocytogenes can translocate the gut, disseminate and transit the blood-brain barrier; 2) evaluate which elements of the host's mucosal immune system may act to prevent and limit infection; 3) determine whether 'innate' or 'natural' immune mechanisms may be effecting at limiting infection by the gut mucosal route; 4) use L. monocytogenes mucosal infections as a model for evaluating whether secretory IgA Abs can effectively contain an infection of the mucosal epithelium by a bacterial intracellular pathogen.