Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
NPJ Biofilms Microbiomes. 2024 Oct 6;10(1):102. doi: 10.1038/s41522-024-00576-8.
The Staphylococcus aureus (S. aureus) SaeRS two-component system (TCS) regulates over 20 virulence factors. While its impact on chronic infection has been thoroughly discussed, its role in the early stage of infection remains elusive. Since macrophages serve as the primary immune defenders at the onset of infection, this study investigates the influence of SaeRS on macrophage functions and elucidates the underlying mechanisms. Macrophage expression of inflammatory and chemotactic factors, phagocytosis, and bactericidal activity against S. aureus were assessed, along with the evaluation of cellular oxidative stress. SaeRS was found to impair macrophage function. Mechanistically, SaeRS inhibited NF-κB pathway activation via toll-like receptor 2 (TLR2). Its immune-modulating effect could partially be explained by the strengthened biofilm formation. More importantly, we found SaeRS compromised macrophage immune functions at early infection stages even prior to biofilm formation. These early immune evasion effects were dependent on bacterial clumping as cytokine secretion, phagocytosis, and bactericidal activity were repaired when clumping was inhibited. We speculate that the bacterial clumping-mediated antigen mask is responsible for SaeRS-mediated immune evasion at the early infection stage. In vivo, ΔsaeRS infection was cleared earlier, accompanied by early pro-inflammatory cytokines production, and increased tissue oxidative stress. Subsequently, macrophages transitioned to an anti-inflammatory state, thereby promoting tissue repair. In summary, our findings underscore the critical role of the SaeRS TCS in S. aureus pathogenicity, particularly during early infection, which is likely initiated by SaeRS-mediated bacterial clumping.
金黄色葡萄球菌（S. aureus）SaeRS 双组分系统（TCS）调节超过 20 种毒力因子。虽然其在慢性感染中的作用已被深入讨论，但它在感染早期阶段的作用仍不清楚。由于巨噬细胞在感染开始时作为主要的免疫防御细胞，因此本研究调查了 SaeRS 对巨噬细胞功能的影响，并阐明了潜在的机制。评估了 SaeRS 对巨噬细胞炎症和趋化因子表达、吞噬作用和金黄色葡萄球菌杀菌活性的影响，同时评估了细胞氧化应激。发现 SaeRS 会损害巨噬细胞功能。在机制上，SaeRS 通过 Toll 样受体 2（TLR2）抑制 NF-κB 途径的激活。其免疫调节作用部分可以通过增强生物膜形成来解释。更重要的是，我们发现即使在生物膜形成之前，SaeRS 在感染早期阶段也会损害巨噬细胞的免疫功能。这些早期的免疫逃避效应依赖于细菌聚集，因为当抑制聚集时，细胞因子分泌、吞噬作用和杀菌活性得到修复。我们推测，细菌聚集介导的抗原掩蔽是 SaeRS 介导的感染早期免疫逃避的原因。在体内，ΔsaeRS 感染更早被清除，同时伴随着早期促炎细胞因子的产生和组织氧化应激的增加。随后，巨噬细胞转变为抗炎状态，从而促进组织修复。总之，我们的研究结果强调了 SaeRS TCS 在金黄色葡萄球菌致病性中的关键作用，特别是在感染早期，这可能是由 SaeRS 介导的细菌聚集引起的。
