Marsh, Elizabeth Kate (2010)
Ph.D. thesis, University of Birmingham.
The nematode Caenorhabditis elegans has been a powerful experimental organism for almost half a century. Over the past ten years, researchers have begun to exploit the power of C. elegans to investigate the biology of a number of human pathogens. This work continues to uncover mechanisms of host immunity and pathogen virulence that are either analogous to those involved during pathogenesis in alternative animal hosts or mechanisms which are, thus far, unique to the worm. In this thesis, we present data that describes an immunological balance in C. elegans, whereby heightened tolerance to one pathogen, the enteric bacteria Salmonella Typhimurium, comes at the cost of increased susceptibility to another, the fatal fungal human pathogen Cryptococcus neoformans. We find that this susceptibility trade-off is mediated by the reciprocal activity of two immune genes: the lysozyme lys-7 and the tyrosine kinase abl-1. We suggest that ABL-1 controls two different DAF-16-dependent pathways to regulate this balance. Both pathways are necessary for wild type resistance to C. neoformans, whilst the activity of only one pathway is a requirement for the tolerance phenotype to S. Typhimurium. We infer from sequence data that LYS-7 has an atypical mode of action in C. elegans, which we hypothesise to be detrimental to the worm during S. Typhimurium pathogenesis and thus a contributing factor to the tolerance phenotype. Furthermore, we find that this tolerance has a Salmonella-dependency which we propose to be under the control of the alternative sigma factor, RpoS. Taken together, we describe an immunological balance in C. elegans for the first time, one that is mediated by both host and pathogen factors. We therefore suggest that the innate immune response of C. elegans has a higher level of immune complexity than previously believed, and that such trade-offs are evolutionarily ancient mechanisms.
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