Peptides derived from Yersinia pestis V-antigen as novel therapeutic interventions for sepsis

Hales, Jack 2021. Peptides derived from Yersinia pestis V-antigen as novel therapeutic interventions for sepsis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Yersinia pestis V-antigen has long been known to modulate the inflammatory response and multiple previous studies have highlighted the importance of V-antigen as a virulence factor for Yersinia spp in vivo. Evidence of a rapid IL-10-mediated immunomodulatory response has been debated due to discrepancies between and within in vivo and in vitro studies and the short-lived nature of the response, however evidence has also emerged of a potent secondary round of immunomodulation that begins after internalisation. This second immunomodulatory effect has never been studied in detail. In this study, using both immortalised and primary human monocytes/monocyte-derived macrophages, the development of V-antigen’s immunomodulation over 16hr was investigated in detail to examine its potential as a therapeutic intervention in highly inflammatory conditions. The analysis revealed a reduction in the secretion in numerous pro- and anti-inflammatory cytokines although a potential increase in IFNγ in response to LPS. The reduction also included IL-10 which did not appear to be responsible for the initial immunomodulation that occurred in primary cells. Investigation into the IL-1β pathway revealed inhibition within the TLR pathway and qPCR gene arrays looking at the expression of genes within the TLR pathway and those related to the inflammasome uncovered peculiarities in expression that suggested an inhibition specific to the MyD88 pathway and evidence of elevated TGFβ signalling. Upon further investigation of secreted cytokines using a TGFβ ELISA, it was shown that V-antigen induced TGFβ secretion to significantly higher levels than control stimulations at 16hr post-introduction. Genes expressing V-antigen fragments derived from a conserved central epitope of V-antigen (aa135-275) were then expressed and tested for their immunomodulatory capabilities through similar stimulations and were found to be capable, to varying degrees, to inhibit cytokine secretion in a similar fashion to the WT, alter gene expression in a similar way, and also induce TGFβ expression

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	30 January 2023
Last Modified:	10 Feb 2024 02:14
URI:	https://orca.cardiff.ac.uk/id/eprint/156324

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