Herpesviruses and Immune Dysregulation in Pulmonary Fibrosis
Abstract
This project represents translational research in the Fiscal Year 2016 Peer Reviewed Medical Research Program topic area of Pulmonary Fibrosis. Pulmonary fibrosis is a progressive disorder that leads to respiratory failure and death in most affected individuals within 2-3 years of diagnosis. Idiopathic pulmonary fibrosis (IPF) is the most common form of progressive pulmonary fibrosis, and currently available treatments modestly slow decline in lung function but do not improve survival or quality of life for IPF patients. It is now widely recognized that recurrent injury to alveolar epithelial cells initiates the process of progressive fibrotic remodeling in IPF; however, the environmental factors that resulted in recurrent cycles of injury repair are not well understood. Previous studies and our preliminary work indicate that reactivation of common herpesviruses (Epstein-Barr Virus and cytomegalovirus) within the lung might act as a source of ongoing lung injury and contribute to the development of pulmonary fibrosis. Most adults have been infected with herpesviruses and these viruses typically remain dormant in the lungs for the remainder of an individual’s lifetime. However, IPF patients have evidence abnormal epithelial cells lining the airspaces of the distal lung, which are characterized by endoplasmic reticulum (ER) stress. We propose that these abnormal epithelial cells can harbor herpesviruses and prevent the body’s immune defenses from suppressing virus replication. Our preliminary studies suggest that T lymphocytes from IPF patients and transgenic mice with abnormal type II alveolar epithelial cells develop “immune exhaustion,” which results from an inability to clear the persistent herpesvirus infection and may contribute to pulmonary fibrosis. Our hypothesis is that ER stress in the lung epithelium, which is common in IPF, allows reactivation of latent herpesviruses, leading to cycles of recurrent injury and repair that drive progressive fibrosis. We plan to utilize samples from patients with IPF and control patient populations to test for evidence of herpesvirus infection in the lungs and determine whether immune response parameters correlate with the presence of herpesviruses in the lungs of IPF patients. In addition, using a mouse model, we will test several novel treatment strategies to determine whether these approaches can improve anti-viral immunity and reduce or prevent lung fibrosis. Together, these proposed studies will show whether anti-herpesvirus immune responses can serve as prognostic biomarkers in IPF and identify IPF patients who could benefit from targeted anti-viral therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710442
Entities
People
- Timothy Blackwell
Organizations
- United States Army
- Vanderbilt University