Outer membrane vesicles containing OmpA induce mitochondrial fragmentation to promote pathogenesis of Acinetobacter baumannii
Varnesh Tiku, Eric M. Kofoed, Donghong Yan, Jing Kang, Min Xu, Mike Reichelt, Ivan Đikić, Man‐Wah Tan
Abstract
Abstract Acinetobacter baumannii is a highly antibiotic resistant Gram-negative bacterium that causes life-threatening infections in humans with a very high mortality rate. A. baumannii is an extracellular pathogen with poorly understood virulence mechanisms. Here we report that A. baumannii employs the release of outer membrane vesicles (OMVs) containing the outer membrane protein A (OmpA Ab ) to promote bacterial pathogenesis and dissemination. OMVs containing OmpA Ab are taken up by mammalian cells where they activate the host GTPase dynamin-related protein 1 (DRP1). OmpA Ab 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 Ab is sufficient to induce mitochondrial fragmentation and cytotoxicity since its expression in E. coli transfers its pathogenic properties to E. coli . A. baumannii infection in mice also induces mitochondrial damage in alveolar macrophages in an OmpA Ab dependent manner. We finally show that OmpA Ab is also required for systemic dissemination in the mouse lung infection model. In this study we uncover the mechanism of OmpA Ab as a virulence factor in A. baumannii infections and further establish the host cell factor required for its pathogenic effects.