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

Varnesh Tiku,Min Xu,Ivan Dikic,Eric M Kofoed,Mike Reichelt,Man-Wah Tan,Jing Kang,Donghong Yan

doi:10.1038/s41598-020-79966-9

Varnesh Tiku, Min Xu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-79966-9

Copy DOI

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.

Highlights

Acinetobacter baumannii is a highly antibiotic resistant Gram-negative bacterium that causes lifethreatening infections in humans with a very high mortality rate
Using genetic and cell biological approaches we demonstrate that outer membrane vesicles (OMVs) containing OmpAAb localize to host cell mitochondria and induce mitochondrial fragmentation and cytotoxicity
In this study we describe how the extracellular bacterial pathogen A. baumannii uses the protein OmpAAb to induce significant changes in mitochondrial morphology and function leading to host cell death and pathogenesis

Summary

Introduction

Acinetobacter baumannii is a highly antibiotic resistant Gram-negative bacterium that causes lifethreatening infections in humans with a very high mortality rate. 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. Strategies employed by A. baumannii to resist antibiotics include the expression of β-lactamases[4], multidrug efflux pumps[5], and aminoglycoside-modifying enzymes[6] Another major attribute leading to widespread persistence of A. baumannii in nosocomial environments is its ability to withstand harsh conditions that can prove to be inhospitable for other pathogens providing A. baumannii with a survival advantage. Purified recombinant O mpAAb protein has been reported to colocalize with mitochondria[20] It is not known if OMVs carrying OmpAAb target host mitochondria in an actual infection with A. baumannii. A handful of bacteria, including H. pylori and L. pneumophila, have been shown to induce mitochondrial fragmentation in a DRP1 dependent m anner[24]

Methods

Results

Conclusion