Submitted on September 11, 2007
Accepted on July 7, 2008
Alveolar Epithelial Cell Injury with Epstein Barr Virus Upregulates TGF
1 Expression
Andrea Patricelli Malizia1, Dominic T Keating2, Sinead M Smith3, Dermot Walls3, Peter P Doran4, and Jim J Egan5*
1 Advanced Lung Disease and Lung Transplant Program, Mater Misericordiae University Hospital, Dublin , Ireland; Genome Research Unit, Mater Misericordiae University Hospital, University College Dublin, Dublin , Republic of Ireland, Ireland
2 Advanced Lung Disease and Lung Transplant Program, Mater Misericordiae University Hospital, Dublin , Ireland
3 School of Biotechnology, Dublin City University, Dublin, Ireland, Ireland
4 Genome Research Unit, Mater Misericordiae University Hospital, University College Dublin, Dublin , Republic of Ireland, Ireland
5 Dublin, Ireland; Advanced Lung Disease and Lung Transplant Program, Mater Misericordiae University Hospital, Dublin , Ireland
* To whom correspondence should be addressed. E-mail: jegan{at}mater.ie.
Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. Epstein-Barr virus (EBV) has previously been localised to alveolar epithelial cells of IPF patients and is associated with a poor prognosis.
In this study we utilised a microarray based differential gene expression analysis strategy to identify molecular drivers of EBV associated lung fibrosis. Two cell lines, primary human alveolar epithelial cells type 2 and A549 cells were infected with EBV.
EBV lytic phase induction increased active and total TGF
1 transcript expression in association with reduced cell proliferation and increased capase 3/7 activity. Exposing EBV infected cells to Ganciclovir resulted in TGF1 de-regulation, and reduced expression of EBV early response genes, BRLF1 and BZLF1. We targeted the BRLF1 and BZLF1 gene products, Rta and Zta, by silencing RNA and this resulted in the normalisation of TGF1 transcript and cell proliferation levels. Our study using a viral cell line model complements existing human and animal model data and further provides evidence to suggest that viral epithelial cell injury may play a role in IPF.
