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Immune responses in a mouse model of Lawsonia intracellularis infection

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MitchellSC_2002redux.pdf (31.43Mb)
Date
2002
Author
Mitchell, Suzanne Christina
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Abstract
 
 
Lawsonia intracellulars is a Gram negative obligate intracellular bacterium and the aetiological agent of proliferative enteropathy (PE, an enteric disease best characterised in pigs). The organism demonstrates tropism for the ileum and colon, multiplying freely in the cytoplasm of immature crypt enterocytes. In infected animals L. intracellulars can be demonstrated consistently intracellularly within the apical cytoplasm of immature crypt epithelial cells, which is associated with increased enterocyte proliferation and the loss of goblet cells. To date characterisation of immune cell infiltration has been rudimentary. Natural infection has been diagnosed in a variety of animals including hamsters, ferrets, horses, emu and deer, but has been most commonly detected in the pig, an animal in which it is prevalent world-wide. Experimentally challenged pigs and hamsters (using pure cultures of bacteria) reproduces the features of natural disease, but successful experimental infection in a mouse model has not been described. The aim of this thesis was to establish an infection system in the mouse and use this to examine the development of infection and lesions of proliferative enteropathy within the gastrointestinal tract. This mouse model was then used to assess the mucosal and serological responses generated by the host in response to inoculation with L. intracellulars.
 
inoculation with L. intracellulars. The infection system demonstrated that 129/Sv/Ev wild-type and isogenic interferon gamma receptor null (IFNγR⁻/⁻) mice developed characteristic lesions of proliferative enteropathy following oral challenge with a pure culture of L. intracellulars (approximately 5xl0⁷ organisms). These were directly comparable to the lesions seen in natural disease with increased proliferation of infected enterocytes in the ileum and colon associated with the loss of goblet cells.
 
Wild-type 129/Sv/Ev mice appeared capable of resolving or resisting infection with this obligate intracellular pathogen, with lesions of proliferative enteropathy detectable only at day 14 or 21 post inoculation, thereafter (days 28 and 35) there were none detectable. In comparison, IFNγR⁻/⁻ mice were highly susceptible to disease and appeared unable to eliminate infection over the time course studied, indicating that a functional IFNγ receptor is necessary in the control o finfection.
 
Immunohistochemical analysis of immune cell markers including CD3⁺, CD4⁺, CD8⁺, γδ TCR⁺ and CD103⁺ cells following inoculation with L. intracellulars was then assessed. Results indicated that there was a marked cellular infiltration following inoculation with L. intracellulars, in both WT and IFNyR"" mice. These changes included statistically significant differences (general linear model, P<0.05) between die CD3⁺, CD4⁺ and CD8⁺ populations ofinoculated and control WT groups over the 28 days assessed, as well as significant changes in the CD4⁺ population between inoculated and control IFNγR⁻/⁻ mice. Notably, post-hoc analysis demonstrated some significant differences in cellular infiltration between infected WT and IFNγR⁻/⁻ mice at 14 days post-inoculation (the only time point where infection was demonstrable in both backgrounds).
 
This novel system is the first detailed description of proliferative enteropathy in mice and has demonstrated the usefulness of this model in the characterisation and analysis of important immunological events during infection with Lawsonia intracellulars.
 
URI
http://hdl.handle.net/1842/29892
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