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

Daxing Gao (1, 2) , Michael J. Ciancanelli (1, 3) , Peng Zhang (1) , Oliver Harschnitz (4) , Vincent Bondet (5) , Mary Hasek (1) , Jie Chen (1) , Xin Mu (6) , Yuval Itan (7) , Aurélie Cobat (8) , Vanessa Sancho-Shimizu (8, 9) , Benedetta Bigio (1) , Lazaro Lorenzo (8) , Gabriele Ciceri (4) , Jessica Mcalpine (4) , Esperanza Anguiano (10) , Emmanuelle Jouanguy (1, 8) , Damien Chaussabel (10, 11, 12) , Isabelle Meyts (13, 14, 7) , Michael S. Diamond (15) , Laurent Abel (1, 8) , Sun Hur (6) , Gregory A. Smith (16) , Luigi Notarangelo (17) , Darragh Duffy (5) , Lorenz Studer (4) , Jean-Laurent Casanova (1, 8, 18, 19) , Shen-Ying Zhang (1, 8)

1 Rockefeller University [New York]
2 USTC - University of Science and Technology of China [Hefei]
3 Turnstone Biologics [New York]
4 Memorial Sloane Kettering Cancer Center [New York]
5 Immunologie Translationnelle - Translational Immunology lab
6 HMS - Harvard Medical School [Boston]
7 MSSM - Icahn School of Medicine at Mount Sinai [New York]
8 Equipe Inserm U1163 - Human genetics of infectious diseases: Complex predisposition
9 Imperial College London
10 BIIR - Baylor Institute for Immunology Research
11 BRI - Benaroya Research Institute [Seattle]
12 Sidra Medicine [Doha, Qatar]
13 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
14 University Hospitals Leuven [Leuven]
15 Washington University School of Medicine in St. Louis
16 Feinberg School of Medicine
17 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
18 Service d'immuno-hématologie pédiatrique [CHU Necker]
19 HHMI - Howard Hughes Medical Institute

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.

Keywords: Immunology; Infectious disease; Innate immunity

Domains: Immunology

Daxing Gao, Michael J. Ciancanelli, Peng Zhang, Oliver Harschnitz, Vincent Bondet, et al.. TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons. Journal of Clinical Investigation, 2021, 131 (1), pp.e134529. ⟨10.1172/JCI134529⟩. ⟨pasteur-03236241⟩