Proinflammatory cytokines as mediators of phenotypic change in bacteria implicated in ventilator-associated pneumonia

Tompsett, A 2021, Proinflammatory cytokines as mediators of phenotypic change in bacteria implicated in ventilator-associated pneumonia , PhD thesis, University of Salford.

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Abstract

Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection in intensive care. VAP is associated with increased hospital stay, healthcare costs, and high mortality. VAP is difficult to diagnose and manage appropriately, leading to widespread empirical broad-spectrum antibiotic use, which contributes to development of antimicrobial resistance in hospitals. We hypothesise that greater understanding of host-microbe interactions (HMI) in the pathogenesis of VAP should dictate appropriate treatment. This thesis begins to address this by investigating the role of host immunity on bacterial physiology. We measured the effects of proinflammatory cytokines (IL-1β, IL-6, TNFα) on three species common in VAP: Staphylococcus aureus, Klebsiella pneumonia, and Pseudomonas aeruginosa. The ability of these cytokines to influence growth, biofilm formation, antimicrobial sensitivity, and rate of antibiotic adaptation was investigated in vitro. The insect infection model Galleria mellonella was modified to investigate antibiotic adaptation in vivo. TNFα significantly increased planktonic growth of all three bacteria, and increased biofilm formation by K. pneumoniae. TNFα was also found to significantly increase minimum inhibitory concentration of meropenem for P. aeruginosa. There was no effect of TNFα on the overall rate of bacterial adaption to meropenem in any species when measured in vitro. However, in G. mellonella, which represents a complex host environment, elevated concentrations of TNFα significantly reduced the rate of S. aureus adaptation to meropenem. These results demonstrate that proinflammatory cytokines may modify clinically important phenotypic characteristics of bacteria implicated in VAP. This work provides a foundation for further development and application of models of increasing complexity to better understand HMI in these infections.

Item Type: Thesis (PhD)
Contributors: Latimer, J (Supervisor), Withers, SB (Supervisor) and Goodhead, IB (Supervisor)
Schools: Schools > School of Environment and Life Sciences
Depositing User: ALEX Tompsett
Date Deposited: 05 Oct 2021 14:48
Last Modified: 05 Oct 2021 14:48
URI: http://usir.salford.ac.uk/id/eprint/61900

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