Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine and Acute Lung Injury Center of Excellence, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
VERSITI Blood Research Institute and Medical College of Wisconsin, Milwaukee, WI, 53233, USA.
Nat Commun. 2024 Jun 3;15(1):4724. doi: 10.1038/s41467-024-48796-y.
Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host's immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs and a prognostically favorable hypoinflammatory plasma biomarker subphenotype. Taken together, our study provides impetus for harnessing the potential of galectin-3-expressing neutrophils to protect from lethal infections and respiratory failure.
铜绿假单胞菌引起的呼吸道感染在住院免疫功能低下和免疫功能正常的机械通气患者中很常见，由于抗生素耐药性，可能会危及生命。这就提出了一个问题，即宿主的免疫系统是否可以通过教育来对抗这种细菌。在这里，我们表明，先前暴露于单一低剂量脂多糖（LPS）可以保护小鼠免受铜绿假单胞菌的致死性感染。LPS 暴露通过促进中性粒细胞和间质巨噬细胞群体的扩张来训练先天免疫系统，这些群体与其他免疫细胞明显不同，其富含吞噬作用和细胞杀伤相关基因的基因集。中性粒细胞群体中的细胞杀伤基因集独特地表达了编码多功能抗菌蛋白半乳糖凝集素-3 的 Lgals3。用于细菌吞噬作用的活体成像、细菌杀伤评估和中性粒细胞相关半乳糖凝集素-3 蛋白水平的检测，以及使用半乳糖凝集素-3 缺陷型小鼠，共同突出了中性粒细胞和半乳糖凝集素-3 作为 LPS 介导的保护作用的核心参与者。急性呼吸衰竭患者的研究结果表明，与非幸存者相比，幸存者的气管吸出物（ETA）中的半乳糖凝集素-3 水平明显更高，ETA 中的半乳糖凝集素-3 水平与中性粒细胞特征强烈相关，并且与预后良好的低炎症血浆生物标志物亚表型相关。总之，我们的研究为利用表达半乳糖凝集素-3 的中性粒细胞来保护免受致命感染和呼吸衰竭提供了动力。
