Acinetobacter baumannii Outer Membrane Protein A Induces Pulmonary Epithelial Barrier Dysfunction and Bacterial Translocation Through The TLR2/IQGAP1 Axis
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 translo...
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Veröffentlicht in: | Frontiers in immunology 2022-06, Vol.13, p.927955-927955 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 1664-3224 1664-3224 |
DOI: | 10.3389/fimmu.2022.927955 |