The regulatory role of the transcription factor PdhR in modulation of bacterial virulence

Wale, Kabo Ronald (2024) The regulatory role of the transcription factor PdhR in modulation of bacterial virulence. PhD thesis, University of Glasgow.

Abstract

An emerging theme in infection biology is the link between metabolic capacity and the ability to colonise specific niches. We previously showed that the transcriptional regulator PdhR was highly downregulated by the pathogen Citrobacter rodentium during colonisation of the murine GI tract. This colonisation is dependent on the type 3 secretion system (T3SS) which is encoded on a pathogenicity island, named the locus of enterocyte effacement (LEE). The T3SS regulation centres on sequential expression of the LEE in response to multitude of signals and cues that are encountered in the intestinal environment of the host. This prompted us to propose that PdhR, could be important in regulation of both metabolism and, directly or indirectly, virulence of C. rodentium. Moreover, given that Citrobacter shares a similar LEE island to E. coli O157, we asked if PdhR controls virulence in both these pathogens. Deletion of pdhR led to a significant decrease in transcript levels of LEE-encoded genes and proteins as elucidated by quantitative reverse transcription PCR and transcriptomic analysis. Cell infection assays demonstrated that loss of pdhR attenuates pathogen colonisation and attachment. We also demonstrated that PdhR directly binds to the ler regulatory region possibly to activate ler transcription, and consequently LEE gene expression. Through transcriptomics we showed that LEE regulation is very complex, and several carbon metabolism pathways maybe wired into global LEE gene regulation in EHEC. Impairing the metabolism of these substrates through deletion of the TF PdhR results in various virulence defects in EHEC and underlies pathogenic outcome of an infection.

Furthermore, it was revealed that PdhR is essential not only for early host colonisation but also required for further persistence of enteric pathogens during host infection. In addition, the pdhR mutant strain showed a lower degree of dysbiosis in the microbial community with no significance at the peak of infection. Thus, this work highlights that PdhR, a transcriptional regulator that is known to regulate central metabolism underpins the intimate relationship between virulence and metabolic flux in EHEC. Potentially understanding this complex relationship could lead to better dietary interventions to reduce EHEC mediated disease.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology; Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Roe, Professor Andrew
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84162
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 26 Mar 2024 16:23
• Last Modified: 26 Mar 2024 16:25
• Thesis DOI: 10.5525/gla.thesis.84162
• URI: https://theses.gla.ac.uk/id/eprint/84162