Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons
Daxing Gao, … , Jean-Laurent Casanova, Shen-Ying Zhang
Daxing Gao, … , Jean-Laurent Casanova, Shen-Ying Zhang
Published November 18, 2020
Citation Information: J Clin Invest. 2021;131(1):e134529. https://doi.org/10.1172/JCI134529.
View: Text | PDF
Research Article Immunology Infectious disease Article has an altmetric score of 35

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

  • Text
  • PDF
Abstract

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3–/– mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell–derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity.

Authors

Daxing Gao, Michael J. Ciancanelli, Peng Zhang, Oliver Harschnitz, Vincent Bondet, Mary Hasek, Jie Chen, Xin Mu, Yuval Itan, Aurélie Cobat, Vanessa Sancho-Shimizu, Benedetta Bigio, Lazaro Lorenzo, Gabriele Ciceri, Jessica McAlpine, Esperanza Anguiano, Emmanuelle Jouanguy, Damien Chaussabel, Isabelle Meyts, Michael S. Diamond, Laurent Abel, Sun Hur, Gregory A. Smith, Luigi Notarangelo, Darragh Duffy, Lorenz Studer, Jean-Laurent Casanova, Shen-Ying Zhang

×

Figure 4

Impact of TLR3 signaling deficiencies on basal IFN-related gene expression.

Options: View larger image (or click on image) Download as PowerPoint
Impact of TLR3 signaling deficiencies on basal IFN-related gene expressi...
mRNA levels of IFNB (A), IFNL1 (B), CXCL10 (C), and IFI44L (D) (relative to GAPDH) in unstimulated fibroblasts from healthy controls (C1–C4) and individuals deficient for TLR3-IFN signaling, as quantified by RT-qPCR with normalization against C1. Representative data from 3 independent experiments are shown. The error bars indicate SDs of triplicate measurements. (E) Gene expression profile of the ISGs differentially expressed in patients with STAT1 (blue bar) and TLR3 (orange bar) deficiencies, relative to mean expression levels in controls, as assessed by RNA-Seq. The heatmap shows the log fold-change in ISG expression, with red indicating upregulation and green downregulation. P values were obtained for likelihood ratio tests by comparing each patient’s fibroblasts with control fibroblasts (A–D), and the respective P values are indicated. **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Posted by 47 X users
Referenced by 1 Bluesky users
71 readers on Mendeley
See more details