ZBP1 regulates cytokine production and cell death in lung fibroblasts following influenza virus infection

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B983
Abstract ID: 4417

Presenting Author:
Summer V Jordan , Ph.D. Student at Univ. of California, Santa Cruz

Abstract:

Regulated cell death following influenza viral infection is an important determinant of disease severity and is required for effective viral clearance. However, extensive cell death can lead to severe tissue damage and compromised lung function. Z-DNA binding protein-1 (ZBP1) is a critical sensor of influenza A virus (IAV) that can activate both apoptotic (non-inflammatory) or necrotic (inflammatory) cell death pathways. The cell type-specific effects of ZBP1 activation during influenza virus infection have not been clearly defined. Here, our single-cell gene expression studies identified lung fibroblasts as a cell type expressing high levels of Zbp1 following IAV infection in vivo. Following infection in vitro, we observed that ~20% of primary lung fibroblasts were readily infected by IAV but did not support high levels of spreading infection. Lung fibroblasts from wildtype mice underwent cell death with ~50% reduction in cell survival at 24 hours while lung fibroblasts from Zbp1 knockout mice were almost completely resistant to cell death. Analysis of cytokine production prior to cell death demonstrated that IAV infection in lung fibroblasts triggered an early ZBP1-dependent production of inflammatory proteins. Knockout of ZBP1 reduced inflammatory cytokine/chemokine production, but left interferon pathways intact. These studies identify lung fibroblasts as a key cell type activating Zbp1-mediated cytokine production and cell death during influenza virus infection.