Crosstalk between host stress-induced translational control and infection by Porphyromonas gingivalis

KNOWLES, Alexander A. (2023). Crosstalk between host stress-induced translational control and infection by Porphyromonas gingivalis. Doctoral, Sheffield Hallam University.

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Abstract

Periodontitis, a chronic inflammatory gum disease, is caused in part by the periodontopathogen Porphyromonas gingivalis. Infection triggers activation of host inflammatory responses which induce stresses such as oxidative stress. Under such conditions, cells can activate the Integrated Stress Response (ISR), a signalling cascade which functions to determine cellular fate, by downregulating protein synthesis and either initiating a stressresponse gene expression program, or if stress cannot be overcome, initiating programmed cell death. Recent studies have implicated the ISR signalling in both host antimicrobial defences and within the pathomechanism of certain microbes. In this study, we investigated how P. gingivalis infection alters translation attenuation during oxidative stress-induced activation of the ISR pathway in oral epithelial cells. P. gingivalis infection alone did not result in ISR activation. In contrast, infection coupled with stress led to differential stress granule formation and composition, along with dysregulation of the microtubule network. Infection also heightened stress-induced translational repression, a response which could not be rescued by ISRIB, a potent ISR inhibitor. Heightened translational repression during stress was observed with both P. gingivalis conditioned media and outer membrane vesicles, implicating the role of a secretory factor, probably proteases known as gingipains, in this exacerbated translational repression. The effects of gingipain inhibitors and gingipains-deficient P. gingivalis mutants further confirmed these pathogen-specific proteases as the effector. Gingipains are known to degrade the mammalian target of rapamycin (mTOR) and these studies implicate the gingipain-mTOR axis as the effector of host translational dysregulation during stress.

Item Type:	Thesis (Doctoral)
Contributors:	Thesis advisor - Stafford, Prachi [0000-0002-9184-6049] (Affiliation: Sheffield Hallam University) Thesis advisor - Campbell, Susan (Affiliation: Sheffield Hallam University) Thesis advisor - Cross, Neil [0000-0003-2055-5815] (Affiliation: Sheffield Hallam University)
Additional Information:	Director of studies: Dr. Prachi Stafford / Supervisors: Dr. Susan Campbell and Dr. Neil Cross.
Research Institute, Centre or Group - Does NOT include content added after October 2018:	Sheffield Hallam Doctoral Theses
Identification Number:	https://doi.org/10.7190/shu-thesis-00535
Depositing User:	Colin Knott
Date Deposited:	04 Aug 2023 16:00
Last Modified:	11 Oct 2023 12:47
URI:	https://shura.shu.ac.uk/id/eprint/32236

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