Outer membrane vesicles containing OmpA induce mitochondrial fragmentation to promote pathogenesis of Acinetobacter baumannii

<jats:title>Abstract</jats:title><jats:p><jats:italic>Acinetobacter baumannii</jats:italic> is a highly antibiotic resistant Gram-negative bacterium that causes life-threatening infections in humans with a very high mortality rate. <jats:italic>A. baumannii</jats:italic> is an extracellular pathogen with poorly understood virulence mechanisms. Here we report that <jats:italic>A. baumannii</jats:italic> employs the release of outer membrane vesicles (OMVs) containing the outer membrane protein A (OmpA<jats:sub>Ab</jats:sub>) to promote bacterial pathogenesis and dissemination. OMVs containing OmpA<jats:sub>Ab</jats:sub> are taken up by mammalian cells where they activate the host GTPase dynamin-related protein 1 (DRP1). OmpA<jats:sub>Ab</jats:sub> mediated activation of DRP1 enhances its accumulation on mitochondria that causes mitochondrial fragmentation, elevation in reactive oxygen species (ROS) production and cell death. Loss of DRP1 rescues these phenotypes. Our data show that OmpA<jats:sub>Ab</jats:sub> is sufficient to induce mitochondrial fragmentation and cytotoxicity since its expression in <jats:italic>E. coli</jats:italic> transfers its pathogenic properties to <jats:italic>E. coli</jats:italic>. <jats:italic>A. baumannii</jats:italic> infection in mice also induces mitochondrial damage in alveolar macrophages in an OmpA<jats:sub>Ab</jats:sub> dependent manner. We finally show that OmpA<jats:sub>Ab</jats:sub> is also required for systemic dissemination in the mouse lung infection model. In this study we uncover the mechanism of OmpA<jats:sub>Ab</jats:sub> as a virulence factor in <jats:italic>A. baumannii</jats:italic> infections and further establish the host cell factor required for its pathogenic effects.</jats:p>