Defining the role of ADAMTS4 in the pathophysiology of Post-Viral Lung Disease 3459

Abstract Description Post-Viral Lung Disease (PVLD) is characterized by persistent inflammation and tissue damage following severe respiratory viral infection. PVLD is a major challenge due to a limited understanding of its mechanisms and lack of effective treatments. Annually, out of ∼500,000 hospitalized influenza patients in the U.S., 25-50% experience respiratory symptoms and long-term sequelae for up to 2 years. We previously identified the extracellular matrix protease ADAMTS4 as a driver of lethal immunopathology in mouse models of acute influenza and a robust predictor of disease severity in humans. Here, our goal was to investigate the role of ADAMTS4 in sustaining inflammation after viral clearance and in contributing to both PVLD and extrapulmonary disease. Our results show that ADAMTS4 levels are significantly upregulated in infected mouse lungs at peak infection (20-fold, 6 dpi) and remain elevated during PVLD (5-fold, 28 dpi). We also observed increased ADAMTS4 expression in the heart (1.5-fold, 6 dpi, 5-fold, 28 dpi), suggesting persistent activity beyond the lungs. ScRNA-seq analyses at 28 dpi identified activated lung fibroblasts as the primary source of ADAMTS4 in PVLD. The frequency of these fibroblasts, as measured by flow cytometry, was significantly elevated in mice who failed to recover from infection. We aim to further explore the mechanisms by which ADAMTS4 sustains lung inflammation in PVLD and the extrapulmonary effects of this pathology. Funding Sources Supported by Startup Funds of the University of California Santa Cruz Topic Categories Viral Immunology (VIR)