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Published on: July 10, 2013
Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure
Sudipta Das1, Tomasz W Kaminski2, Brent T Schlegel3
1Division 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.
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.
Insights
Prior exposure to lipopolysaccharide (LPS) trains the innate immune system, enhancing neutrophil and macrophage defenses against lethal Pseudomonas aeruginosa infections. This LPS-mediated protection involves galectin-3, a key antibacterial protein, offering a novel therapeutic strategy.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Pseudomonas aeruginosa respiratory infections pose a life-threatening risk, particularly in hospitalized patients due to antibiotic resistance.
- The potential for immune system education to combat P. aeruginosa remains an important research question.
Purpose of the Study:
- To investigate whether prior exposure to lipopolysaccharide (LPS) can protect against lethal P. aeruginosa infection.
- To elucidate the underlying innate immune mechanisms, focusing on neutrophils, macrophages, and galectin-3.
Main Methods:
- Mice were exposed to a low dose of LPS prior to lethal P. aeruginosa challenge.
- Immune cell populations, gene expression (phagocytosis, cell-killing), and galectin-3 levels were analyzed.
- Intravital imaging, bacterial killing assays, and galectin-3-deficient mice were utilized.
- Human patient data (endotracheal aspirates) from acute respiratory failure cases were analyzed for galectin-3 and immune cell signatures.
Main Results:
- LPS pre-exposure conferred protection against lethal P. aeruginosa infection in mice.
- LPS trained the innate immune system, expanding neutrophil and interstitial macrophage populations with enhanced phagocytic and cell-killing gene expression.
- Neutrophils uniquely expressed Lgals3 (encoding galectin-3), a critical component of LPS-mediated protection.
- Elevated galectin-3 levels in endotracheal aspirates correlated with survival and a favorable hypoinflammatory subphenotype in patients with acute respiratory failure.
Conclusions:
- Prior LPS exposure effectively trains innate immunity, conferring protection against lethal P. aeruginosa infection.
- Neutrophils and the antibacterial protein galectin-3 are central to this LPS-induced protective mechanism.
- Galectin-3 levels in respiratory secretions may serve as a prognostic biomarker for patients with acute respiratory failure.
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