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

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Dikic,  Ivan
Max Planck Fellow Group ER remodelling Group, Prof. Ivan Đikić, Max Planck Institute of Biophysics, Max Planck Society;
Department of Infectious Diseases, Genentech Inc., South San Francisco, CA, USA;
Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany;
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany;

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Citation

Tiku, V., Kofoed, E. M., Yan, D., Kang, J., Xu, M., Reichelt, M., et al. (2021). Outer membrane vesicles containing OmpA induce mitochondrial fragmentation to promote pathogenesis of Acinetobacter baumannii. Scientific Reports, 11(1): 618. doi:10.1038/s41598-020-79966-9.


Cite as: http://hdl.handle.net/21.11116/0000-0007-AF2C-4
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 (OmpAAb) to promote bacterial pathogenesis and dissemination. OMVs containing OmpAAb are taken up by mammalian cells where they activate the host GTPase dynamin-related protein 1 (DRP1). OmpAAb 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 OmpAAb 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 OmpAAb dependent manner. We finally show that OmpAAb is also required for systemic dissemination in the mouse lung infection model. In this study we uncover the mechanism of OmpAAb as a virulence factor in A. baumannii infections and further establish the host cell factor required for its pathogenic effects.