Medicine (St Vincent's) - Theses

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    Characterisation of susceptibility to Listeria monocytogenes infection in the non-obese diabetic (NOD) mouse
    WANG, NANCY ( 2012)
    The immune system has evolved the ability to prevent infection by a wide range of pathogens while maintaining tolerance to self-tissues. Due to the strong selective pressure imposed by microbial pathogens, susceptibility to infection can be modulated by a large number of genetic loci. It is postulated that, at least in some cases, allelic variants for particular loci confer increased resistance to pathogens while simultaneously increasing the risk of developing autoimmune diseases. A number of recently discovered disease loci appear to act as “genetic pivot points” between pathogen defence and autoimmune pathogenesis. It is anticipated that characterising these loci will provide novel insights regarding the interplay between immune and autoimmune responses, as well as reveal potential therapeutic targets for treating both infectious and autoimmune diseases. Murine models provide a complementary approach to human studies for investigating genetic and cellular mechanisms that underlie susceptibility to infectious and autoimmune diseases. The non-obese diabetic (NOD) mouse strain is one of the best-characterised models of type 1 diabetes (T1D), an autoimmune disease caused by the destruction of insulin-producing pancreatic β cells. Similar to humans, predisposition to T1D is attributed to multiple genetic loci in NOD mice. Intriguingly, non-diabetogenic mouse strains can also harbour diabetogenic alleles for some T1D susceptibility loci. Using congenic mice, our laboratory confirmed that non-diabetogenic C57BL/6 (B6) mice harbour a diabetogenic allele for a T1D susceptibility locus on chromosome (Chr) 13, termed Idd14. Coincidentally, the Idd14 locus overlapped with Listr2, a proposed susceptibility locus for Listeria monocytogenes, which is an extensively studied intracellular bacterial pathogen. Notably, B6 mice are resistant to L. monocytogenes infection, whereas NOD mice are reported as susceptible. We therefore hypothesised that allelic variation for this interval, which increases T1D risk, would confer resistance against L. monocytogenes in NOD mice. The goal of this study was to investigate the biological and genetic effects of allelic variation for Idd14/Listr2 in NOD mice for L. monocytogenes infection and T1D. Towards this goal, the first aim was to investigate the immunological basis of susceptibility to L. monocytogenes in NOD mice. In comparison to infected B6 mice, infected NOD mice exhibited reduced antigen-specific CD8+ T-cell responses, which was associated with apparent deficiencies in dendritic cells. Infected NOD mice also exhibited exacerbated neutrophilia, a potential compensatory mechanism in susceptible hosts. The second aim was to determine the role of neutrophils during L. monocytogenes infection. Specific depletion of neutrophils impaired bacterial clearance in susceptible NOD mice, but not in resistant B6 mice, demonstrating that neutrophils are essential for controlling L. monocytogenes infection in susceptible hosts. In addition, NOD macrophages exhibited impaired antimicrobial function. These results indicate that neutrophils may compensate for deficient T-cell and macrophage responses to ensure host survival during L. monocytogenes infection. The third aim was to confirm the Listr2 locus using congenic NOD mouse strains, which harbour different B6-derived Chr 13 interval, and determine if the refined intervals for Listr2 and Idd14 continue to co-localise. Concurrently, it was found that the Idd14 locus could be dissected into two sub-loci, Idd14.1 and Idd14.2. Listr2 was confirmed and co-localised with Idd14.1 to an overlapping interval (~ 18 Mb) on Chr 13. This co-localisation raises the intriguing possibility that allele variation for the same gene(s) within this interval affects both infection and autoimmune disease susceptibility.