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Author Notes:

Z.L., E.J.G.R., O.H., H.G., Y.-H.C., N.K., M.L.H., K.D., M.M., D.L., P.B., J.C., Y.S.L., S.K.K., S.Z., L.L., R.C., F.R., R.P.D., R.D.D., N.M., V.B., G.A.S., L.D.N., E.S.M., L.S., S.-Y.Z., and J.-L.C. performed or supervised experiments, generated and analyzed data, and contributed to the manuscript by providing figures and tables. D.R., D.M., Y.S., B.M., A.C. and L.A. performed computational analysis of data. L.M., C.G., J.-L.S., S.B. and S.C. evaluated and recruited patients. Z.L, J.-L.C and S.-Y.Z., wrote the manuscript. J.-L.C. and S.-Y.Z. conceptualized and supervised the project. All the authors edited the manuscript.

We warmly thank our patients and their families. We thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions; Tatiana Kochetkov for technical assistance; Yelena Nemirovskaya for administrative assistance. We thank the Bio-Imaging, Flow Cytometry Resource Center and Genomics Resource Center of The Rockefeller University for technical assistance. We thank Dusan Bogunovic for providing the human fibroblast cells with complete TBK1 deficiency.

Gregory A. Smith discloses a significant financial interest in Thyreos, Inc. All other authors declare no competing interests.

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Research Funding:

This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program, grant UL1TR001866, NIH grants R01AI088364, R01NS072381, R01AI020211 and R21AI151663, grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01), the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02), and CNSVIRGEN (ANR-19-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cité University, and the St. Giles Foundation. LDN is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Y.H.C. was supported by the A*STAR International Fellowship (AIF). P.B. was supported by the FRM (EA20170638020) and the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt Schueller). E.S.M. is supported by NIH grant R01AI020211.

Keywords:

  • Humans
  • Cell Death
  • Encephalitis, Herpes Simplex
  • Herpes Simplex
  • Herpesvirus 1, Human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Tumor Necrosis Factor, Type I
  • Toll-Like Receptor 3

Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency

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Journal Title:

Science Immunology

Volume:

Volume 8, Number 82

Publisher:

, Pages eade2860-eade2860

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422∗) and frameshift (P493fs9∗) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422∗ and P493fs9∗ RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAImediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-â and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.

Copyright information:

© 2024 American Association for the Advancement of Science. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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