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Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity

Abstract

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/β immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.

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Acknowledgements

I thank Jean-Laurent Casanova for critical reading of this manuscript. I thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions, and technical and administrative assistance. I would also like to thank the patients and their families for participating in our studies. Our work on the human genetics of herpes simplex encephalitis 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 (UL1TR001866), NIH (R21NS084255, R01AI088364 and R01NS072381), the French National Research Agency (ANR) (ANR-14-CE14-0008-01, AAPG2018-SEAeHostFactors, AAPG2019-CNSVIRGEN and ANR-10-LABX-62-IBEID), the Thrasher Research Fund, the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St Giles Foundation.

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Zhang, S. Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity. Hum Genet (2020). https://doi.org/10.1007/s00439-020-02127-5

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