Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA.
Department of Chemical & Biological Engineering and Clinical &Translational Research Center, State University of New York, Buffalo, NY, 14260 USA.
Mol Immunol. 2021 Mar;131:68-77. doi: 10.1016/j.molimm.2020.12.012. Epub 2020 Dec 25.
Phagocytic cells are critical to host defense against Pseudomonas aeruginosa, a Gram-negative bacterium that is an opportunistic pathogen. Accordingly, susceptible individuals frequently have impaired innate immune responses, including those with cystic fibrosis or neutropenia. Previous studies identified that the downregulation, or loss, of bacterial flagellar motility enables bacteria to evade interactions with phagocytic cells that result in phagocytic uptake of the bacteria. However, the mechanistic bases for motility-dependent interactions between P. aeruginosa and host cell surfaces that lead to phagocytic uptake of the bacteria are poorly understood. A recent insight is that exogenous addition of a negatively charged phospholipid, phosphatidylinositol-(3,4,5)-triphosphate (PIP), promotes the engagement of non-motile strains of P. aeruginosa with phagocytes leading to uptake of the bacteria. Thus, we hypothesized that the engagement of P. aeruginosa by phagocytic cells is mediated by motility-dependent interactions with cell-surface polyanions. Here we report that endogenous polyanionic N-linked glycans and heparan sulfate mediate bacterial binding of P. aeruginosa by human monocytic cells. These specific interactions resulted in P. aeruginosa phagocytosis, bacterial type 3 secretion system (T3SS)-mediated cellular intoxication and the IL-1β response of host innate immune cells. Importantly, the bacterial interactions with the glycans were motility-dependent and could be recapitulated with purified, immobilized glycans. Therefore, this work describes novel interactions of P. aeruginosa with specific phagocyte cell-surface glycans that modulate relevant host innate immune responses to the bacteria, including phagocytosis, inflammation and cytotoxicity.
吞噬细胞对于宿主防御铜绿假单胞菌（一种革兰氏阴性菌，机会性病原体）至关重要。因此，易感染个体通常会出现先天免疫应答受损，包括囊性纤维化或中性粒细胞减少症患者。先前的研究表明，细菌鞭毛运动能力的下调或丧失可使细菌逃避与吞噬细胞的相互作用，从而避免被吞噬细胞吞噬。然而，导致细菌被吞噬的铜绿假单胞菌与宿主细胞表面之间依赖运动的相互作用的机制基础还知之甚少。最近的一项发现是，外加带负电荷的磷脂酰肌醇-(3,4,5)-三磷酸（PIP）可促进非运动型铜绿假单胞菌菌株与吞噬细胞的结合，导致细菌被吞噬。因此，我们假设吞噬细胞与铜绿假单胞菌的结合是由与细胞表面多阴离子的运动依赖性相互作用介导的。在这里，我们报告内源性带负电荷的 N 连接聚糖和肝素硫酸盐介导人单核细胞对铜绿假单胞菌的细菌结合。这些特定的相互作用导致铜绿假单胞菌的吞噬作用、细菌 III 型分泌系统（T3SS）介导的细胞中毒以及宿主先天免疫细胞的 IL-1β 反应。重要的是，细菌与聚糖的相互作用依赖于运动能力，并且可以用纯化的固定化聚糖来再现。因此，这项工作描述了铜绿假单胞菌与特定吞噬细胞表面糖的新型相互作用，这些相互作用调节了宿主对细菌的相关先天免疫反应，包括吞噬作用、炎症和细胞毒性。
