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.
Abstract
Influenza A virus damages tight junctions, and specifically claudin-4, of respiratory epithelial cells http://ow.ly/UyGD5
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: K.R. Short is supported by a National Health and Medical Research Council (Canberra, Australia) C.J. Martin post-doctoral fellowship (1054081). This study was funded in part by the European Union Seventh Framework Programme project ANTIGONE (grant agreement number 278976), and by the VIRGO consortium, which is funded by the Netherlands Genomics Initiative and by the Dutch Government (project number FES0908). S. Herold is funded by the German Research Foundation (SFB TR84 B2 and SFB 1021 C5) and the German Center for Lung Research (DZL). M. Bárcena is supported by a Netherlands Organisation for Scientific Research (NWO) MEERVOUD-836.10.003 grant. Funding information for this article has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received August 3, 2015.
- Accepted November 3, 2015.
- Copyright ©ERS 2016