2. Academic Validation
  3. Single-cell heterogeneity in interferon induction potential is heritable and governed by variation in cell state

Single-cell heterogeneity in interferon induction potential is heritable and governed by variation in cell state

  • bioRxiv. 2025 Dec 22:2025.12.09.693293. doi: 10.64898/2025.12.09.693293.
Elizabeth A Thayer 1,  Gabriela Shipman 1,  Joel Rivera-Cardona 1,  Tarun Mahajan 2 3,  Qi Wen Teo 3 4,  J Sebastian Paez 5,  Joseph Lederer 3,  Jie Chen 6 7 8,  Nicholas C Wu 3 4 7 9,  Sergei Maslov 2 3 9 10,  Christopher B Brooke 1 3
Affiliations

Affiliations

  • 1 Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 2 Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 3 Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 4 Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 5 Talus Bioscience, Seattle, WA, USA.
  • 6 Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 7 Department of Biomedical and Translational Sciences, Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
  • 8 Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 9 Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
  • 10 Department of Physics, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
PMID: 41415397 DOI: 10.64898/2025.12.09.693293
Abstract

Type I and III interferons (IFNs) are among the first lines of defense against viral Infection, yet they are generally only produced by a tiny fraction of infected cells. Here, we show that cellular heterogeneity in IFN induction potential upon treatment with immunostimulatory RNA is not due to variability in sensing of stimuli but instead is shaped by heterogeneity in tonic cell signaling state. Using complementary single-cell approaches, we found that baseline variation in the c-Jun N-terminal kinase (JNK) and activator protein (AP)-1 transcription factor families correlated with IFNL1 expression predisposition. We further show that drug-based inhibition of JNK signaling virtually eliminates the innate Antiviral response to immunostimulatory RNA. Finally, we show that single cell heterogeneity in IFN induction potential is heritable and stably maintained over numerous generations. Together, our study emphasizes the influence of intrinsic variability in cell state on innate immune regulation and IFN induction heterogeneity.

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