Galectin-3 Marks Protection from Lethal Bacterial Infection in Mice and Acute Respiratory Failure in Humans

Infection by the Gram-negative bacterium Pseudomonas aeruginosa is common in hospitalized immunocompromised as well as immunocompetent ventilated patients and is often life-threatening because of resistance of the bacteria to antibiotics. This prompts the question whether the host’s immune system can be educated to combat this bacterium. Bacterial lipopolysaccharide (LPS) is known to promote host resistance to bacterial infections although an understanding of the underlying mechanism is lacking. Here we show that prior exposure to a single low dose of LPS protects mice from a lethal infection by P. aeruginosa. These mice displayed expansion of a neutrophil and an interstitial macrophage population that were barely detectable in mice that did not receive LPS prior to infection. Both cell populations were distinguishable from other immune cell populations by being enriched in gene sets that included 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 of neutrophils 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. Interrogating the relevance of these findings in hospitalized 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. Taken together, our study provides impetus to harnessing the potential of galectin-3-expressing neutrophils to protect the lung from lethal infections and respiratory failure.