2. Academic Validation
  3. Acinetobacter baumannii Outer Membrane Protein A Induces Pulmonary Epithelial Barrier Dysfunction and Bacterial Translocation Through The TLR2/IQGAP1 Axis

Acinetobacter baumannii Outer Membrane Protein A Induces Pulmonary Epithelial Barrier Dysfunction and Bacterial Translocation Through The TLR2/IQGAP1 Axis

  • Front Immunol. 2022 Jun 30:13:927955. doi: 10.3389/fimmu.2022.927955.
Wang Zhang 1 2 3,  Hua Zhou 4,  Yan Jiang 1 2 3,  Jintao He 1 2 3,  Yue Yao 1 2 3,  Jianfeng Wang 5,  Xiaochen Liu 1 2 3,  Sebastian Leptihn 1 6 7,  Xiaoting Hua 1 2 3,  Yunsong Yu 1 2 3
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China.
  • 4 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Department of Respiratory and Critical Care Medicine, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China.
  • 6 Zhejiang University-University of Edinburgh Institute, Zhejiang University, Haining, China.
  • 7 University of Edinburgh Medical School, Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
PMID: 35844614 DOI: 10.3389/fimmu.2022.927955
Abstract

Pulmonary epithelial barrier dysfunction is a critical pathophysiological process in pneumonia and associated invasive infections, such as those caused by Acinetobacter baumannii. However, the mechanisms underlying A. baumannii-induced pulmonary epithelial barrier dysfunction and Bacterial translocation remain unclear. In this study, lungs of mice and A549 human epithelial cell monolayers were challenged with the A. baumannii wild-type strain and an outer membrane protein A (ompA) deletion strain. In addition, epithelial cells in culture were treated with purified OmpA protein or transfected with a eukaryotic expression vector encoding ompA (pCMV-ompA). Bacterial translocation across cell monolayers and intrapulmonary burden were measured, barrier function was evaluated in vivo and in vitro; cell migration ability was determined. The specific inhibitors C29 and JSH-23 were used to suppress the activity of Toll-like Receptor 2 (TLR2) and of NF-κB, respectively. IQ-GTPase-activating protein 1 (IQGAP1) small interfering RNA was used to knock down endogenous IQGAP1 expression. In this work, we show that OmpA from A. baumannii increased the production of pro-inflammatory cytokines, remodeled the Cytoskeleton, and internalized intercellular adherens junctions (AJs); these changes eventually induced pulmonary epithelial barrier dysfunction to promote Bacterial translocation. IQGAP1-targeting small interfering RNA and chemical inhibition of TLR2 or NF-κB prevented high permeability of the pulmonary epithelial barrier. TLR2/NF-κB signaling was involved in OmpA-induced inflammation, IQGAP1-mediated OmpA-induced opening of the pulmonary epithelial barrier via Cytoskeleton dynamic remodeling, and cellular redistribution of the major AJ protein, E-cadherin. These observations indicate that A. baumannii uses OmpA to overcome epithelial defences and cross the pulmonary epithelial barrier.

Keywords

Acinetobacter baumannii; bacterial translocation; cytoskeleton; epithelial barrier; outer membrane protein A.

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