Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions
Top Cited Papers
- 7 January 2016
- journal article
- research article
- Published by European Respiratory Society (ERS) in European Respiratory Journal
- Vol. 47 (3), 954-966
- https://doi.org/10.1183/13993003.01282-2015
Abstract
A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial–endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear. Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelial–endothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV was added to the upper chamber. We showed that the addition of IAV (H1N1 and H5N1 subtypes) resulted in significant barrier damage. Interestingly, we found that, while endothelial cells mounted a pro-inflammatory/pro-coagulant response to a viral infection in the adjacent epithelial cells, damage to the alveolar epithelial–endothelial barrier occurred independently of endothelial cells. Rather, barrier damage was associated with disruption of tight junctions amongst epithelial cells, and specifically with loss of tight junction protein claudin-4. Taken together, these data suggest that maintaining epithelial cell integrity is key in reducing pulmonary oedema during IAV infection.Keywords
Funding Information
- German Center for Lung Research
- German Research Foundation (SFB TR84 B2 and SFB 1021 C5)
- Netherlands Genomics Initiative (FES0908)
- European Union FP7 project ANTIGONE (278976)
- NHMRC C.J. Martin post-doctoral fellowship (1054081)
- NWO (NWO-MEERVOUD-836.10.003)
This publication has 40 references indexed in Scilit:
- Influenza virus and endothelial cells: a species specific relationshipFrontiers in Microbiology, 2014
- Pathogenesis of influenza-induced acute respiratory distress syndromeThe Lancet Infectious Diseases, 2014
- Japanese Encephalitis Virus Disrupts Cell-Cell Junctions and Affects the Epithelial Permeability Barrier FunctionsPLOS ONE, 2013
- Influenza Infects Lung Microvascular Endothelium Leading to Microvascular Leak: Role of Apoptosis and Claudin-5PLOS ONE, 2012
- West Nile Virus Infection Causes Endocytosis of a Specific Subset of Tight Junction Membrane ProteinsPLOS ONE, 2012
- The Avian Influenza Virus NS1 ESEV PDZ Binding Motif Associates with Dlg1 and Scribble To Disrupt Cellular Tight JunctionsJournal of Virology, 2011
- Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus InfectionCell, 2011
- Lung Pathology in Fatal Novel Human Influenza A (H1N1) InfectionAmerican Journal of Respiratory and Critical Care Medicine, 2010
- Rhinovirus Disrupts the Barrier Function of Polarized Airway Epithelial CellsAmerican Journal of Respiratory and Critical Care Medicine, 2008
- Apoptosis and Pathogenesis of Avian Influenza A (H5N1) Virus in HumansEmerging Infectious Diseases, 2007