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Contrasting effects of linezolid on healthy and dysfunctional human neutrophils: reducing C5a-induced injury

Lookup NU author(s): Professor John Simpson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2020, The Author(s).Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP). Patients with VAP have poorly functioning neutrophils, related to increased levels of the complement fragment C5a. The antibiotic linezolid has been useful in controlling MRSA-related VAP infections; however clinical benefit does not always correlate with antimicrobial effect, suggesting the possibility of immunomodulatory properties. Here the effects of linezolid on healthy and dysfunctional neutrophils (modelled by C5a-induced injury) was investigated. Functional assays (killing, phagocytosis, transmigration, and respiratory burst) were used to assess the effects of pre-, co- and post-incubating linezolid (0.4–40 mg/L) with healthy neutrophils relative to those with C5a-induced injury. C5a decreased neutrophil killing, and phagocytosis of MRSA. Furthermore, C5a significantly decreased neutrophil transmigration to IL-8, but did not affect respiratory burst. Co-incubation of linezolid significantly improved killing of MRSA by dysfunctional neutrophils, which was supported by concomitant increases in phagocytosis. Conversely linezolid impaired killing responses in healthy neutrophils. Pre- or post-incubation of linezolid prior or following C5a induced injury had no effect on neutrophil function. This study suggests that linezolid has immunomodulatory properties that protect human neutrophils from injury and provides insight into its mode of action beyond a basic antibiotic.


Publication metadata

Author(s): Evans SJ, Roberts AEL, Morris AC, Simpson AJ, Harris LG, Mack D, Jenkins RE, Wilkinson TS

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2020

Volume: 10

Issue: 1

Print publication date: 01/12/2020

Online publication date: 02/10/2020

Acceptance date: 26/08/2020

Date deposited: 17/12/2020

ISSN (electronic): 2045-2322

Publisher: Nature Research

URL: https://doi.org/10.1038/s41598-020-72454-0

DOI: 10.1038/s41598-020-72454-0

PubMed id: 33009444


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