Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase

Stéphanie Bibert; Mathieu Quinodoz; Sylvain Perriot; Fanny S Krebs; Maxime Jan; Rita C Malta; Emilie Collinet; Mathieu Canales; Amandine Mathias; Nicole Faignart; Eliane Roulet-Perez; Pascal Meylan; René Brouillet; Onya Opota; Leyder Lozano-Calderon; Florence Fellmann; Nicolas Guex; Vincent Zoete; Sandra Asner; Carlo Rivolta; Renaud Du Pasquier; Pierre-Yves Bochud

doi:10.1038/s41467-024-48287-0

Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase

Nat Commun. 2024 May 10;15(1):3969. doi: 10.1038/s41467-024-48287-0.

Authors

Stéphanie Bibert¹, Mathieu Quinodoz^#^{2

3

4}, Sylvain Perriot^#⁵, Fanny S Krebs^{6

7}, Maxime Jan⁸, Rita C Malta⁹, Emilie Collinet¹, Mathieu Canales⁵, Amandine Mathias⁵, Nicole Faignart¹⁰, Eliane Roulet-Perez¹⁰, Pascal Meylan¹¹, René Brouillet¹¹, Onya Opota¹¹, Leyder Lozano-Calderon¹, Florence Fellmann¹², Nicolas Guex⁸, Vincent Zoete^{6

7

13}, Sandra Asner^{1

9}, Carlo Rivolta^{2

3

4}, Renaud Du Pasquier^{5

14}, Pierre-Yves Bochud¹⁵

Affiliations

¹ Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
² Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
³ Department of Ophthalmology, University of Basel, Basel, Switzerland.
⁴ Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
⁵ Department of Clinical Neurosciences, Laboratory of Neuroimmunology, Neuroscience Research Centre, University Hospital and University of Lausanne, Lausanne, Switzerland.
⁶ Department of Oncology UNIL-CHUV, Computer-Aided Molecular Engineering, University of Lausanne, Lausanne, Switzerland.
⁷ Ludwig Institute for Cancer Research, Lausanne, Switzerland.
⁸ Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
⁹ Pediatric Infectious Diseases and Vaccinology Unit, Woman-Mother-Child Department, University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁰ Department of Pediatrics, Child Neurology Unit, University Hospital and University of Lausanne, Lausanne, Switzerland.
¹¹ Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland.
¹² The ColLaboratory, University of Lausanne, Lausanne, Switzerland.
¹³ Molecular Modelling Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
¹⁴ Department of Clinical Neurosciences, Service of Neurology, University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁵ Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland. Pierre-Yves.Bochud@chuv.ch.

^# Contributed equally.

Abstract

Encephalitis is a rare and potentially fatal manifestation of herpes simplex type 1 infection. Following genome-wide genetic analyses, we identified a previously uncharacterized and very rare heterozygous variant in the E3 ubiquitin ligase WWP2, in a 14-month-old girl with herpes simplex encephalitis. The p.R841H variant (NM_007014.4:c.2522G > A) impaired TLR3 mediated signaling in inducible pluripotent stem cells-derived neural precursor cells and neurons; cells bearing this mutation were also more susceptible to HSV-1 infection compared to control cells. The p.R841H variant increased TRIF ubiquitination in vitro. Antiviral immunity was rescued following the correction of p.R841H by CRISPR-Cas9 technology. Moreover, the introduction of p.R841H in wild type cells reduced such immunity, suggesting that this mutation is linked to the observed phenotypes.

Publication types

Research Support, Non-U.S. Gov't
Case Reports

MeSH terms

CRISPR-Cas Systems
Encephalitis, Herpes Simplex* / genetics
Female
Herpesvirus 1, Human* / genetics
Humans
Induced Pluripotent Stem Cells / metabolism
Infant
Mutation*
Neural Stem Cells / metabolism
Neural Stem Cells / virology
Neurons / metabolism
Toll-Like Receptor 3 / genetics
Toll-Like Receptor 3 / metabolism
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism
Ubiquitination

Substances

Ubiquitin-Protein Ligases
Toll-Like Receptor 3
TLR3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding