Abstract
Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in humans. It is life-threatening and has a first peak of incidence in childhood, during primary infection. Children with HSE are not particularly prone to other infections, including HSV-1 infections of tissues other than the brain. About 8–10% of childhood cases are due to monogenic inborn errors of 19 genes, two-thirds of which are recessive, and most of which display incomplete clinical penetrance. Childhood HSE can therefore be sporadic but genetic, enabling new diagnostic and therapeutic approaches. In this Review, we examine essential cellular and molecular mechanisms of cell-intrinsic antiviral immunity in the brain that are disrupted in individuals with HSE. These mechanisms include both known (such as mutations in the TLR3 pathway) and previously unknown (such as the TMEFF1 restriction factor) antiviral pathways, which may be dependent (for example, IFNAR1) or independent (for example, through RIPK3) of type I interferons. They operate in cortical or brainstem neurons, and underlie forebrain and brainstem infections, respectively. Conversely, the most severe inborn errors of leukocytes, including a complete lack of myeloid and/or lymphoid blood cells, do not underlie HSE. Thus congenital defects in intrinsic immunity in brain-resident neurons that underlie HSE broaden natural host defences against HSV-1 from the leukocytes of the immune system to other cells in the organism.
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Acknowledgements
The authors thank the patients and their families for their trust and participation in our studies; L. Notarangelo, G. Smith and L. Studer for their collaboration in studies of the cellular basis of HSE; L. Abel, M. Tardieu, P. Lebon and F. Rozenberg, with whom we built and studied the French HSE cohort; past and present HSE team members, in particular E. Jouanguy, S. Plancoulaine, V. Sancho-Shimizu, R. P. de Diego, M. Herman, E. Pauwels, F. G. Lafaille, H. K. Lim, Y.-S. Lee, P. Bastard, D. Gao, Z. Liu and Y. H. Chan for their energy and enthusiasm; all members of both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions and technical assistance; and the administrative teams of both our laboratories, in particular Y. Nemirovskaya and L. Lorenzo, for their invaluable support. Our work on the human genetics of HSE 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, R21AI151663, R01AI088364 and R01NS072381), the Starr Foundation Tri-Institutional Stem Cell Initiative (2021-019), the French National Research Agency (ANR) (ANR-10-IAHU-01, ANR-21-RHUS-08, ANR-14-CE14-0008-01, AAPG2018-SEAeHostFactors, AAPG2019-CNSVIRGEN and ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the Square Foundation, the SCOR Corporate Foundation for Science, William E. Ford, General Atlantic’s Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic’s Co-President, Managing Director and Head of Business in EMEA, and the General Atlantic Foundation, the Battersea and Bowery Advisory Group, the Elizabeth Hall Janeway Award from the Kellen Women’s Entrepreneurship Fund, the Stavros Niarchos Foundation (SNF) as part of its grant to the SNF Institute for Global Infectious Disease Research at The Rockefeller University, the Thrasher Research Fund, the Rockefeller University, the Howard Hughes Medical Institute, Institut National de la Santé et de la Recherche Médicale (INSERM), the Imagine Institute, Paris Cité University and the St Giles Foundation.
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Zhang, SY., Casanova, JL. Genetic defects of brain immunity in childhood herpes simplex encephalitis. Nature 635, 563–573 (2024). https://doi.org/10.1038/s41586-024-08119-z
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DOI: https://doi.org/10.1038/s41586-024-08119-z
