Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure

Sudipta Das, Tomasz W. Kaminski, Brent T. Schlegel, William Bain, Sanmei Hu, Akruti Patel, Sagar L. Kale, Kong Chen, Janet S. Lee, Rama K. Mallampalli, Valerian E. Kagan, Dhivyaa Rajasundaram, Bryan J. McVerry, Prithu Sundd, Georgios D. Kitsios, Anuradha Ray and Prabir Ray ()
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Sudipta Das: University of Pittsburgh School of Medicine
Tomasz W. Kaminski: VERSITI Blood Research Institute and Medical College of Wisconsin
Brent T. Schlegel: University of Pittsburgh School of Medicine
William Bain: University of Pittsburgh School of Medicine
Sanmei Hu: University of Pittsburgh School of Medicine
Akruti Patel: University of Pittsburgh School of Medicine
Sagar L. Kale: University of Pittsburgh School of Medicine
Kong Chen: University of Pittsburgh School of Medicine
Janet S. Lee: Washington University School of Medicine
Rama K. Mallampalli: The Ohio State University (OSU)
Valerian E. Kagan: University of Pittsburgh
Dhivyaa Rajasundaram: University of Pittsburgh School of Medicine
Bryan J. McVerry: University of Pittsburgh School of Medicine
Prithu Sundd: VERSITI Blood Research Institute and Medical College of Wisconsin
Georgios D. Kitsios: University of Pittsburgh School of Medicine
Anuradha Ray: University of Pittsburgh School of Medicine
Prabir Ray: University of Pittsburgh School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48796-y

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