Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of Francisella tularemia.

摘要: Francisella tularensis(Ft) is a highly virulent, intracellular Gram-negative bacterial pathogen. Acute Ft infection by aerosol route causes pneumonic tularemia, characterized nodular hemorrhagic lesions, neutrophil-predominant influx, necrotic debris, fibrin deposition, and severe alveolitis. suppresses activity of neutrophils impairing their respiratory burst phagocytic activity. However, the fate massive numbers recruited to site unclear. Here, we show that resulted in prominent induction neutrophil extracellular traps (NETs) within damaged lungs mice infected with live attenuated vaccine strain Ft(Ft-LVS), as well domestic cats rabbits naturally Ft. Further, Ft-LVS increased lung myeloperoxidase (MPO) activity, which mediates histone protein degradation during NETosis anchors chromatin scaffolds NETs. In addition, also induced expression peptidylarginine deiminase 4, an enzyme citrullination histones formation The released NETs were found largely attached alveolar epithelium, disrupted thin epithelial barrier. Furthermore, concentration-dependent release from vitro. Pharmacological blocking MPO reduced Ft-induced release, whereas addition H2O2 (a substrate MPO) significantly augmented thus indicating critical role Although immunofluorescence electron microscopy revealed could efficiently trap bacteria, failed exert bactericidal effects. Taken together, these findings suggest exacerbate tissue damage pulmonary infection, targeting may offer novel therapeutic interventions alleviating damage.