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.
|Suter, Steven E; Gouthro, Terry A; O'Malley, Thomas et al. (2007) Marking of peripheral T-lymphocytes by retroviral transduction and transplantation of CD34+ cells in a canine X-linked severe combined immunodeficiency model. Vet Immunol Immunopathol 117:183-96|
|Suter, S E; Gouthro, T A; McSweeney, P A et al. (2006) Optimized transduction of canine paediatric CD34(+) cells using an MSCV-based bicistronic vector. Vet Res Commun 30:881-901|
|Hallman, Troy M; Peng, Min; Meade, Ray et al. (2006) The mitochondrial and kidney disease phenotypes of kd/kd mice under germfree conditions. J Autoimmun 26:1-6|
|Cruickshank, Sheena M; English, Nicholas R; Felsburg, Peter J et al. (2005) Characterization of colonic dendritic cells in normal and colitic mice. World J Gastroenterol 11:6338-47|
|Lan, Jing-Gang; Cruickshank, Sheena-Margaret; Singh, Joy-Carmelina-Indira et al. (2005) Different cytokine response of primary colonic epithelial cells to commensal bacteria. World J Gastroenterol 11:3375-84|
|Krakowka, Steven; Felsburg, Peter (2005) Gnotobiotics and immunopathology: the use of the gnotobiotic environment to study acquired and inherited immunodeficiency diseases. Vet Immunol Immunopathol 108:165-75|
|Suter, Steven E; Gouthro, Terry A; McSweeney, Peter A et al. (2004) Isolation and characterization of pediatric canine bone marrow CD34+ cells. Vet Immunol Immunopathol 101:31-47|
|Cruickshank, S M; McVay, L D; Baumgart, D C et al. (2004) Colonic epithelial cell mediated suppression of CD4 T cell activation. Gut 53:678-84|
|Ashcroft, A J; Cruickshank, S M; Croucher, P I et al. (2003) Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity 19:849-61|
|Felsburg, Peter J; Hartnett, Brian J; Gouthro, Terry A et al. (2003) Thymopoiesis and T cell development in common gamma chain-deficient dogs. Immunol Res 27:235-46|
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