Department of Microbiology and Immunology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.
Department of Cell Biology & Physiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.
Microbiol Spectr. 2022 Jun 29;10(3):e0085822. doi: 10.1128/spectrum.00858-22. Epub 2022 May 16.
Interactions between Staphylococcus aureus and the host immune system can have significant impacts on antibiotic efficacy, suggesting that targeting and modulating the immune response to S. aureus infection may improve antibiotic efficacy and improve infection outcome. As we've previously shown, high levels of reactive oxygen species (ROS), associated with an M1-like proinflammatory macrophage response, potently induce antibiotic tolerance in S. aureus. Although the proinflammatory immune response is critical for initial control of pathogen burden, recent studies demonstrate that modulation of the macrophage response to an anti-inflammatory, or M2-like, response facilitates resolution of established S. aureus skin and soft tissue infections, arthritis, and bacteremia. Here, we evaluated the impact of host-directed immunosuppressive chemotherapeutics and anti-inflammatory agents on antibiotic efficacy against S. aureus. Staphylococcus aureus is the leading cause of hospital-acquired infections in the United States with high rates of antibiotic treatment failure. Macrophages represent an important intracellular niche in experimental models of S. aureus bacteremia. Although a proinflammatory macrophage response is critical for controlling infection, previous studies have identified an antagonistic relationship between antibiotic treatment and the proinflammatory macrophage response. Reactive oxygen species, produced by macrophages during respiratory burst, coerce S. aureus into an antibiotic tolerant state, leading to poor treatment outcome. Here, we aimed to determine the potential of host-directed immunomodulators that reduce the production of reactive oxygen species to improve antibiotic efficacy against intracellular S. aureus.
金黄色葡萄球菌与宿主免疫系统之间的相互作用会对抗生素疗效产生重大影响，这表明靶向和调节金黄色葡萄球菌感染的免疫反应可能会提高抗生素疗效并改善感染结果。正如我们之前所表明的，与 M1 样促炎巨噬细胞反应相关的高水平活性氧 (ROS) 可强烈诱导金黄色葡萄球菌对抗生素产生耐受性。虽然促炎免疫反应对于初始控制病原体负担至关重要，但最近的研究表明，调节巨噬细胞对抗炎（或 M2 样）反应的反应有助于解决已建立的金黄色葡萄球菌皮肤和软组织感染、关节炎和菌血症。在这里，我们评估了宿主定向免疫抑制化疗药物和抗炎剂对金黄色葡萄球菌抗生素疗效的影响。金黄色葡萄球菌是美国医院获得性感染的主要原因，抗生素治疗失败率很高。巨噬细胞代表金黄色葡萄球菌菌血症实验模型中的一个重要细胞内小生境。尽管促炎巨噬细胞反应对于控制感染至关重要，但先前的研究已经确定了抗生素治疗与促炎巨噬细胞反应之间的拮抗关系。巨噬细胞在呼吸爆发期间产生的活性氧会迫使金黄色葡萄球菌进入抗生素耐受状态，导致治疗效果不佳。在这里，我们旨在确定减少活性氧产生的宿主定向免疫调节剂改善针对细胞内金黄色葡萄球菌的抗生素疗效的潜力。
