Gelsolin protects mitochondria and regulates inflammation during Legionella pneumophila infection

Legionella pneumophila ( L. pneumophila ) is the causative agent of Legionnaires’ disease, a severe bacterial pneumonia. Difficulty in diagnosing Legionnaires’ disease leads to an underreporting of cases and delayed treatment. Rapid-acting, broad-spectrum therapies are needed to treat pathology while avoiding antibiotic resistance. We showed that gelsolin knockout ( gsn ^-/- ) mice succumb more quickly to severe L. pneumophila infection despite no difference in bacterial loads in the lung compared to wild type mice. There is an increase in CXCL1/KC production from macrophages from gsn ^-/- mice, which is accompanied by increased neutrophils and apoptosis in their lungs. Neutrophils lacking gelsolin produce fewer neutrophil extracellular traps, and their mitochondrial capacity is diminished in response to L. pneumophila . Gelsolin is required for maintaining mitochondrial network morphology and respiration in L. pneumophila infected macrophages. When given recombinant gelsolin protein, gsn ^-/- mice survive significantly longer during severe L. pneumophila infection, with reduced lung pathology, and the inflammatory signature of their macrophages was reduced in vitro . Together, gelsolin protects mice during severe L. pneumophila infection, dampens inflammation, promotes mitochondrial health, and maintains neutrophil function.