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Molecular and functional characterisation of the immunodominant antigens of the obligate intracellular pathogen Lawsonia Intracellularis

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McAllisterG_2006redux.pdf (17.51Mb)
Date
2006
Author
McAllister, Georgina
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Abstract
 
 
Lawsonia intracellularis is an obligately intracellular pathogen which is the cause of the disease complex known as proliferative enteropathy (PE) or ileitis. This bacterium is pathogenic in a broad range of animal hosts, disease being most notable in pigs. L. intracellularis has a tropism for immature (crypt) epithelial cells and disease is characterised by epithelial hyperplasia in infected crypts. This pathology presumably reflects expression of novel virulence factors during infection. To date few genes have been identified and of these only IsaA, a tlyA homologue, has any function ascribed. TlyA proteins of bacteria belong to a novel family identified across a phylogenetically diverse range of bacteria. These include several gastrointestinal pathogens such as Helicobacter pylori, Campylobacterjejuni, Brachyspira hyodysenteriae and Lawsonia intracellularis. These proteins have been identified mainly through genomic sequencing and their expression and role(s) during infection remain to be fully defined. TlyA deletion mutants in H. pylori and B. hyodysenteriae are attenuated, suggesting that these proteins perform important roles during infection. LsaA (lawsonia surface antigen) the L. intracellularis orthologue, is expressed during infection in vitro and in vivo, which suggests that this factor is involved during adherence and/or invasion of intestinal epithelial cells. The principal aim was to characterise function(s) of LsaA. Specifically the putative function as an adhesin was investigated further using a combination of biochemical and molecular approaches (including affinity purification and yeast 2- hybrid analysis) to elucidate possible receptor(s). However, no consistent partner was evident therefore mammalian epithelial cell receptors could not be defined using this range of approaches. It is possible that LsaA's role in adherence is adventitious - for example, it has been proposed that the TlyA family of proteins possess a regulatory role in bacterial colonisation as opposed to a direct involvement in bacterial adherence. The existence of two conserved putative functional domains, S4 RNA binding and methyltransferase motifs have been noted in all members of the TlyA family examined to date. These domains are found separately in several protein families known to be involved in gene regulation. Since no system has been developed for mutating genes in L. intracellularis the proteome of a TlyA deletion mutant of H. pylori was compared to its parent to further this potentially new and interesting function of TlyA family proteins Notably, flagellin B and catalase were absent in the tlyA mutant. Since deletion of tlyA corresponds with changes in expression of several H. pylori genes, it can be concluded that reduced colonisation of H. pylori tlyA mutant is likely to be as a result of effects on expression of virulence genes rather than a direct role in adherence.
 
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http://hdl.handle.net/1842/35184
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