Cellular Senescence Dysregulates Antiviral Interferon Responses in Idiopathic Pulmonary Fibrosis.
6 affiliations
- 1Buck Institute for Research on Aging, Novato, California, USA.
- 2Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
- 3Institute of Medical Microbiology, Jena University Hospital, Jena, Germany.
- 4Cedars-Sinai, Los Angeles, California, USA.
- 5University of California, San Francisco, San Francisco, California, USA.
- 6California Pacific Medical Center, Research Institute, San Francisco, California, USA.
Abstract
Patients with idiopathic pulmonary fibrosis (IPF) are highly vulnerable to respiratory virus infections, but the cellular mechanisms linking fibrotic remodeling to impaired local antiviral defense remain unclear. Here, we investigated how cellular senescence shapes the response of patient-derived healthy (HLF) and IPF primary lung fibroblasts to influenza A virus (IAV) infection. Transcriptomic profiling identified infection as the driver of gene expression in both DNA damage-induced senescent HLF and IPF fibroblasts and revealed induction of canonical antiviral pathways in both cell states. However, senescent IPF fibroblasts adopted a distinct antiviral response state characterized by a broader set of uniquely induced genes and differential coordination of antiviral transcriptional networks. Functionally, senescence increased viral titers in HLF and IPF fibroblasts, while senescent IPF fibroblasts displayed an altered inflammatory response. Network analysis linked viral response- and cell cycle-associated modules specifically to the senescent HLF infected state, whereas these programs were weaker in senescent IPF fibroblasts. Transcription factor inference identified IRF3 and STAT1 as candidate regulators of this altered antiviral state in both senescent HLF and IPF fibroblasts. Consistent with the network and transcription factor analyses, siRNA-mediated depletion of IRF3 or STAT1 significantly reduced IFN-β secretion in senescent HLF fibroblasts, whereas IPF fibroblasts showed only milder effects, indicating a disease-specific dependence on these pathways for antiviral control. Together, these findings show that the combination of cellular senescence and fibrotic fibroblast identity creates a dysfunctional antiviral state that may help explain the high susceptibility of IPF patients to virus-associated acute exacerbations and disease worsening.
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BibTeX
@article{hughes2026cellular,
title = {{Cellular Senescence Dysregulates Antiviral Interferon Responses in Idiopathic Pulmonary Fibrosis.}},
author = {Jun-Wei B Hughes and Yasmina Reisser and Franziska Hornung and Tyler A U Hilsabeck and Fiona Senchyna and Ana L Coelho and Tsung-Che Ho and Kevin Schneider and David Furman and Cory M Hogaboam and Claude Jourdan Le Saux and Pierre-Yves Desprez and Stefanie Deinhardt-Emmer},
journal = {Aging cell},
year = {2026},
month = oct,
doi = {10.1111/acel.70763},
url = {https://europepmc.org/article/MED/42902866},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cellular Senescence Dysregulates Antiviral Interferon Responses in Idiopathic Pulmonary Fibrosis.
AU - Jun-Wei B Hughes
AU - Yasmina Reisser
AU - Franziska Hornung
AU - Tyler A U Hilsabeck
AU - Fiona Senchyna
AU - Ana L Coelho
AU - Tsung-Che Ho
AU - Kevin Schneider
AU - David Furman
AU - Cory M Hogaboam
AU - Claude Jourdan Le Saux
AU - Pierre-Yves Desprez
AU - Stefanie Deinhardt-Emmer
PY - 2026
DA - 2026/10/30
JO - Aging cell
DO - 10.1111/acel.70763
UR - https://europepmc.org/article/MED/42902866
AB - Patients with idiopathic pulmonary fibrosis (IPF) are highly vulnerable to respiratory virus infections, but the cellular mechanisms linking fibrotic remodeling to impaired local antiviral defense remain unclear. Here, we investigated how cellular senescence shapes the response of patient-derived healthy (HLF) and IPF primary lung fibroblasts to influenza A virus (IAV) infection. Transcriptomic profiling identified infection as the driver of gene expression in both DNA damage-induced senescent HLF and IPF fibroblasts and revealed induction of canonical antiviral pathways in both cell states. However, senescent IPF fibroblasts adopted a distinct antiviral response state characterized by a broader set of uniquely induced genes and differential coordination of antiviral transcriptional networks. Functionally, senescence increased viral titers in HLF and IPF fibroblasts, while senescent IPF fibroblasts displayed an altered inflammatory response. Network analysis linked viral response- and cell cycle-associated modules specifically to the senescent HLF infected state, whereas these programs were weaker in senescent IPF fibroblasts. Transcription factor inference identified IRF3 and STAT1 as candidate regulators of this altered antiviral state in both senescent HLF and IPF fibroblasts. Consistent with the network and transcription factor analyses, siRNA-mediated depletion of IRF3 or STAT1 significantly reduced IFN-β secretion in senescent HLF fibroblasts, whereas IPF fibroblasts showed only milder effects, indicating a disease-specific dependence on these pathways for antiviral control. Together, these findings show that the combination of cellular senescence and fibrotic fibroblast identity creates a dysfunctional antiviral state that may help explain the high susceptibility of IPF patients to virus-associated acute exacerbations and disease worsening.
SN - 1474-9718
SN - 1474-9726
ER -