Microbiology and Infectious Disease, Institute of Life Science, Swansea University Medical School, Floor 1, Room 137, Singleton Park, Swansea, SA2 8PP, UK.
Division of Anaesthesia, Department of Medicine, School of Clinical Medicine, University of Cambridge, Level 4, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hills Road, Box 93, Cambridge, CB2, 0QQ, UK.
Sci Rep. 2020 Oct 2;10(1):16377. doi: 10.1038/s41598-020-72454-0.
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.
耐甲氧西林金黄色葡萄球菌（MRSA）是呼吸机相关性肺炎（VAP）的重要病因。患有 VAP 的患者中性粒细胞功能不良，这与补体片段 C5a 水平升高有关。抗生素利奈唑胺在控制 MRSA 相关 VAP 感染方面很有用；然而，临床获益并不总是与抗菌效果相关，这表明其可能具有免疫调节特性。本研究旨在探讨利奈唑胺对健康和功能失调中性粒细胞（通过 C5a 诱导损伤建模）的影响。功能测定（杀伤、吞噬、迁移和呼吸爆发）用于评估健康中性粒细胞与 C5a 诱导损伤的中性粒细胞预先、共同和后孵育利奈唑胺（0.4-40mg/L）的效果。C5a 降低了中性粒细胞对 MRSA 的杀伤和吞噬作用。此外，C5a 显著降低了中性粒细胞向 IL-8 的迁移，但不影响呼吸爆发。利奈唑胺共同孵育可显著改善功能失调中性粒细胞对 MRSA 的杀伤作用，同时吞噬作用也相应增加。相反，利奈唑胺损害了健康中性粒细胞的杀伤反应。在 C5a 诱导损伤之前或之后预先或随后孵育利奈唑胺对中性粒细胞功能没有影响。这项研究表明，利奈唑胺具有免疫调节特性，可保护人中性粒细胞免受损伤，并深入了解其作用模式超越了基本抗生素。
