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

Author:

Bibert StéphanieORCID,Quinodoz Mathieu,Perriot Sylvain,Krebs Fanny S.,Jan MaximeORCID,Malta Rita C.,Collinet Emilie,Canales Mathieu,Mathias AmandineORCID,Faignart NicoleORCID,Roulet-Perez Eliane,Meylan Pascal,Brouillet René,Opota Onya,Lozano-Calderon Leyder,Fellmann FlorenceORCID,Guex NicolasORCID,Zoete Vincent,Asner Sandra,Rivolta CarloORCID,Du Pasquier Renaud,Bochud Pierre-YvesORCID

Abstract

AbstractEncephalitis 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.

Funder

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Fondation Leenaards

Fondation Santos-Suarez pour la Recherche Médicale

Publisher

Springer Science and Business Media LLC

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