The role of Epstein-Barr virus latent membrane protein 1 in idiopathic pulmonary fibrosis and viral latency maintenance
Description
The Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus for which an estimated 90% of the human population is seropositive by adulthood. EBV has been implicated in a number of lymphocyte and epithelial malignancies and is considered the causative agent in anaplastic nasopharyngeal carcinoma. Evidence of EBV has been detected in the lungs of Idiopathic Pulmonary Fibrosis (IPF) patients at a higher rate than control and detection of the EBV protein Latent Membrane Protein 1 (LMP1) suggests a poorer prognosis which raises the questions whether, and how, EBV is involved in the pathogenesis of IPF. This study proposes a possible mechanism of progression of IPF through repeated alveolar epithelial insult followed by aberrant wound healing and decline in function involving synergy between LMP1 and the profibrotic cytokine TGF-beta1. LMP1 was shown to synergistically increase expression of the pro-fibrotic markers fibronectin EDA and matrix metalloproteinase 9 while additively increasing levels of PAI-1. Additionally, co-treatment with LMP1 and TGF-beta1 promote the loss of the epithelial markers E-Cadherin, zona occluding 1, surfactant protein C, and the gain of mesenchymal markers N-Cadherin, vimentin and alpha smooth muscle actin, resulting in epithelial to mesenchymal transition (EMT). Inhibition of the ERK pathway protected from LMP1/TGF-beta1 induced EMT while inhibition of the NF-kappaB pathway protected from the LMP1 contribution without affecting TGF-beta1 signaling. LMP1 reduced levels of the cytoplasmic isoform of the promyelocytic leukemia protein (PML) and disrupted the canonical TGF-beta1 signaling pathway LMP1 increased the levels of nuclear PML and intensity of the PML nuclear bodies (PML NB). Considered as part of the interferon response to viral infection, PML NB are dynamic multifunctional proteinaceous nuclear domains that affect processes as diverse as transcription, apoptosis and telomere regulation. Additionally, herpes viruses disrupt PML NB during lytic reactivation and utilize the remnants of these domains as replication compartments. Disruption of PML NB by arsenic trioxide (ATO) induced lytic reactivation of EBV in alveolar epithelial and nasopharyngeal carcinoma cells. Additionally, treatment with ATO conferred susceptibility to the antiherpesviral ganciclovir. To our knowledge, this is the first report of upregulation of PML NB by a viral protein to maintain latency