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Title: Identification and characterisation of bacterial TIR domains, with particular focus on Yersinia pestis
Author: Spear, Abigail Mary
ISNI:       0000 0004 2712 8258
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2011
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The Toll/IL-l Receptor (TIR) domain is an essential signalling module in eukaryotic innate immune signalling pathways. Homotypic interaction between TIR domains allows the formation of a signalling platform in which molecules are able to interact and activate each other to initiate an immune signalling cascade. Proteins containing TIR domains have also been discovered in bacteria. Studies have subsequently shown that these proteins are able to modulate mammalian immune signalling pathways dependent on TIR interactions and that this forms an evasion strategy for bacterial pathogens. In this study a bioinformatic search for proteins containing TIR domains was carried out across unicellular organisms, including bacteria. TIR domain proteins (Tdps) from highly pathogenic bacteria were down-selected for investigation. After an initial screen of their activity, a Tdp from Yersinia pestis, the causative agent of plague, was down-selected for further investigation. The bioinformatic analysis found a high representation of Tdps in bacteria generally classified as non-pathogens, and that TIR domains are promiscuous in their co-occurrence with other domains. This analysis also showed that they are not necessarily conserved between strains and species. These findings question the universal role of Tdps in the pathogenic evasion of a host immune response and suggest they may have other functions. Initial screening of down-selected Tdps showed that they were able to modulate immune signalling pathways in vitro, but studies with a Tdp-deficient mutant of Y. pestis did not demonstrate a role for this protein in the virulence of Y. pestis in a mouse model. However, this Tdp-deficient mutant did display two characteristics in vitro: an increased autoaggregation phenotype when compared to wild-type Y. pestis and an inability to survive as well as wild-type bacteria in conditions of high salinity. These fmdings indicate that TIR domain proteins may have other roles in bacterial physiology unrelated to immune evasion.
Supervisor: Atkins, H. ; Bancroft, G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral