Abstract：
Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose-dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow-derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N-acetyl-L- cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A-induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.
摘要：
金黄色葡萄球菌（S。金黄色葡萄球菌）肺炎已成为一个日益重要的公共卫生问题。最近的证据表明，表观遗传修饰在宿主针对病原体感染的免疫防御中至关重要。在这项研究中,我们发现金黄色葡萄球菌感染以剂量依赖的方式诱导组蛋白去乙酰化酶6(HDAC6)的表达。此外，通过使用金黄色葡萄球菌肺炎小鼠模型，我们发现HDAC6抑制剂，妥司他丁A,在金黄色葡萄球菌肺炎中表现出保护作用，降低肺结构的死亡率和破坏，减少肺部细菌负担并抑制炎症反应。原发性骨髓源性巨噬细胞的机制研究表明，HDAC6抑制剂，tubastatinA和tubacin,通过促进细菌清除而不是调节吞噬作用来减少细胞内细菌负荷。最后,N-乙酰-L-半胱氨酸,一种广泛使用的活性氧（ROS）清除剂，拮抗ROS的产生，并显着抑制tubastatinA诱导的金黄色葡萄球菌清除率。这些发现表明HDAC6抑制剂通过诱导ROS促进巨噬细胞的杀菌活性,金黄色葡萄球菌清除和生产的重要宿主因子。我们的研究将HDAC6确定为预防金黄色葡萄球菌感染的合适表观遗传修饰靶标，和作为治疗金黄色葡萄球菌肺炎的有用化合物的tubastatinA。
