Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597921
Title: Induction of cell death in macrophages by Salmonella enterica serovar Typhimurium
Author: Cook, P. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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Abstract:
The aim of this thesis was to study the response of macrophages to infection with Salmonella enterica serovar Typhimurium and to determine whether TLR signalling contributes to the induction of cell death in infected macrophages. When macrophages were infected with wild-type S. Typhimurium, cell death occurred within two hours of infection. This was dependent on the bacterial protein SipB and required caspase-1 activity. At two-hours post-infection, little or no cell death was observed in macrophages infected with a sipB-deficient mutant of S. Typhimurium C5. Cell death was triggered by this mutant by 24-hours post-infection. The role of TLR4 in S. Typhimurium-induced cell death was investigated using macrophages from TLR4 knockout mice. At 24 hours, induction of cell death by S. Typhimurium C5-sipB in TLR4-deficient cells was reduced compared to wild-type controls. Activated TLR4 recruits the adapter proteins MyD88, Mal. Trif and Tram. The induction of cell death in macrophages deficient for each of these adapters was studied.  Preliminary data suggest that signalling through Trif and Tram contributes to the induction of cell death in infected macrophages. MAPK inhibitors were used to investigate the role of MAPK signalling in S. Typhimurium-induced cell death pathways. Specific inhibition of p38 MAPK by SB203580 increased the level of cytotoxicity in infected macrophages. However, PD98059, which inhibits activation of p38, ERK and JNK, had no effect on cell death suggesting that MAPK proteins are involved in both pro-survival and pro-cell death pathways. Inhibition of p38 signalling alone interferes with survival pathways and tilts the balance towards cell death.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.597921  DOI: Not available
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