Centre for Bacterial Resistance Biology, Imperial College London, London, United Kingdom.
mBio. 2024 Aug 14;15(8):e0164324. doi: 10.1128/mbio.01643-24. Epub 2024 Jul 23.
The bacterial pathogen responds to the host environment by increasing the thickness of its cell wall. However, the impact of cell wall thickening on susceptibility to host defenses is unclear. Using bacteria incubated in human serum, we show that host-induced increases in cell wall thickness led to a reduction in the exposure of bound antibody and complement and a corresponding reduction in phagocytosis and killing by neutrophils. The exposure of opsonins bound to protein antigens or lipoteichoic acid (LTA) was most significantly reduced, while opsonization by IgG against wall teichoic acid or peptidoglycan was largely unaffected. Partial digestion of accumulated cell wall using the enzyme lysostaphin restored opsonin exposure and promoted phagocytosis and killing. Concordantly, the antibiotic fosfomycin inhibited cell wall remodeling and maintained the full susceptibility of to opsonophagocytic killing by neutrophils. These findings reveal that host-induced changes to the cell wall reduce the ability of the immune system to detect and kill this pathogen through reduced exposure of protein- and LTA-bound opsonins.
Understanding how bacteria adapt to the host environment is critical in determining fundamental mechanisms of immune evasion, pathogenesis, and the identification of targets for new therapeutic approaches. Previous work demonstrated that remodels its cell envelope in response to host factors and we hypothesized that this may affect recognition by antibodies and thus killing by immune cells. As expected, incubation of in human serum resulted in rapid binding of antibodies. However, as bacteria adapted to the serum, the increase in cell wall thickness resulted in a significant reduction in exposure of bound antibodies. This reduced antibody exposure, in turn, led to reduced killing by human neutrophils. Importantly, while antibodies bound to some cell surface structures became obscured, this was not the case for those bound to wall teichoic acid, which may have important implications for vaccine design.
细菌病原体通过增加细胞壁的厚度来响应宿主环境。然而，细胞壁增厚对宿主防御能力的影响尚不清楚。我们使用在人血清中孵育的细菌表明，宿主诱导的细胞壁增厚导致结合抗体和补体的暴露减少，相应地减少中性粒细胞的吞噬和杀伤作用。结合蛋白抗原或脂磷壁酸（LTA）的调理素的暴露减少最为显著，而针对壁磷壁酸或肽聚糖的 IgG 的调理作用基本不受影响。使用溶葡萄球菌酶部分消化积累的细胞壁可恢复调理素暴露并促进吞噬和杀伤作用。相应地，抗生素磷霉素抑制细胞壁重塑并维持 对中性粒细胞的调理吞噬杀伤的完全敏感性。这些发现表明，宿主诱导的 细胞壁变化通过减少蛋白和 LTA 结合的调理素的暴露，降低了免疫系统检测和杀死这种病原体的能力。
