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

Zhiyong Liu; Eduardo J.Garcia Reino; Oliver Harschnitz; Hongyan Guo; Yi Hao Chan; Noopur V. Khobrekar; Mary L. Hasek; Kerry Dobbs; Darawan Rinchai; Marie Materna; Daniela Matuozzo; Danyel Lee; Paul Bastard; Jie Chen; Yoon Seung Lee; Seong K. Kim; Shuxiang Zhao; Param Amin; Lazaro Lorenzo; Yoann Seeleuthner; Remi Chevalier; Laure Mazzola; Claire Gay; Jean Louis Stephan; Baptiste Milisavljevic; Soraya Boucherit; Flore Rozenberg; Rebeca Perez de Diego; Richard D. Dix; Nico Marr; Vivien Béziat; Aurelie Cobat; Mélodie Aubart; Laurent Abel; Stephane Chabrier; Gregory A. Smith; Luigi D. Notarangelo; Edward S. Mocarski; Lorenz Studer; Jean Laurent Casanova; Shen Ying Zhang

doi:10.1126/sciimmunol.ade2860

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

Zhiyong Liu, Eduardo J.Garcia Reino, Oliver Harschnitz, Hongyan Guo, Yi Hao Chan, Noopur V. Khobrekar, Mary L. Hasek, Kerry Dobbs, Darawan Rinchai, Marie Materna, Daniela Matuozzo, Danyel Lee, Paul Bastard, Jie Chen, Yoon Seung Lee, Seong K. Kim, Shuxiang Zhao, Param Amin, Lazaro Lorenzo, Yoann SeeleuthnerRemi Chevalier, Laure Mazzola, Claire Gay, Jean Louis Stephan, Baptiste Milisavljevic, Soraya Boucherit, Flore Rozenberg, Rebeca Perez de Diego, Richard D. Dix, Nico Marr, Vivien Béziat, Aurelie Cobat, Mélodie Aubart, Laurent Abel, Stephane Chabrier, Gregory A. Smith, Luigi D. Notarangelo, Edward S. Mocarski, Lorenz Studer, Jean Laurent Casanova^*, Shen Ying Zhang^*

^*Corresponding author for this work

Microbiology-Immunology

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English (US)
Article number	eade2860
Journal	Science Immunology
Volume	8
Issue number	82
DOIs	https://doi.org/10.1126/sciimmunol.ade2860
State	Published - Apr 2023

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/sciimmunol.ade2860

Cite this

Liu, Z., Reino, E. J. G., Harschnitz, O., Guo, H., Chan, Y. H., Khobrekar, N. V., Hasek, M. L., Dobbs, K., Rinchai, D., Materna, M., Matuozzo, D., Lee, D., Bastard, P., Chen, J., Lee, Y. S., Kim, S. K., Zhao, S., Amin, P., Lorenzo, L., ... Zhang, S. Y. (2023). Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency. Science Immunology, 8(82), Article eade2860. https://doi.org/10.1126/sciimmunol.ade2860

@article{9bb9e62f07a0487cbb8f6e83027760a8,

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

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-{\^a} 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.",

author = "Zhiyong Liu and Reino, {Eduardo J.Garcia} and Oliver Harschnitz and Hongyan Guo and Chan, {Yi Hao} and Khobrekar, {Noopur V.} and Hasek, {Mary L.} and Kerry Dobbs and Darawan Rinchai and Marie Materna and Daniela Matuozzo and Danyel Lee and Paul Bastard and Jie Chen and Lee, {Yoon Seung} and Kim, {Seong K.} and Shuxiang Zhao and Param Amin and Lazaro Lorenzo and Yoann Seeleuthner and Remi Chevalier and Laure Mazzola and Claire Gay and Stephan, {Jean Louis} and Baptiste Milisavljevic and Soraya Boucherit and Flore Rozenberg and {de Diego}, {Rebeca Perez} and Dix, {Richard D.} and Nico Marr and Vivien B{\'e}ziat and Aurelie Cobat and M{\'e}lodie Aubart and Laurent Abel and Stephane Chabrier and Smith, {Gregory A.} and Notarangelo, {Luigi D.} and Mocarski, {Edward S.} and Lorenz Studer and Casanova, {Jean Laurent} and Zhang, {Shen Ying}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors.",

year = "2023",

month = apr,

doi = "10.1126/sciimmunol.ade2860",

language = "English (US)",

volume = "8",

journal = "Science Immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "82",

}

Liu, Z, Reino, EJG, Harschnitz, O, Guo, H, Chan, YH, Khobrekar, NV, Hasek, ML, Dobbs, K, Rinchai, D, Materna, M, Matuozzo, D, Lee, D, Bastard, P, Chen, J, Lee, YS, Kim, SK, Zhao, S, Amin, P, Lorenzo, L, Seeleuthner, Y, Chevalier, R, Mazzola, L, Gay, C, Stephan, JL, Milisavljevic, B, Boucherit, S, Rozenberg, F, de Diego, RP, Dix, RD, Marr, N, Béziat, V, Cobat, A, Aubart, M, Abel, L, Chabrier, S, Smith, GA, Notarangelo, LD, Mocarski, ES, Studer, L, Casanova, JL & Zhang, SY 2023, 'Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency', Science Immunology, vol. 8, no. 82, eade2860. https://doi.org/10.1126/sciimmunol.ade2860

TY - JOUR

T1 - Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency

AU - Liu, Zhiyong

AU - Reino, Eduardo J.Garcia

AU - Harschnitz, Oliver

AU - Guo, Hongyan

AU - Chan, Yi Hao

AU - Khobrekar, Noopur V.

AU - Hasek, Mary L.

AU - Dobbs, Kerry

AU - Rinchai, Darawan

AU - Materna, Marie

AU - Matuozzo, Daniela

AU - Lee, Danyel

AU - Bastard, Paul

AU - Chen, Jie

AU - Lee, Yoon Seung

AU - Kim, Seong K.

AU - Zhao, Shuxiang

AU - Amin, Param

AU - Lorenzo, Lazaro

AU - Seeleuthner, Yoann

AU - Chevalier, Remi

AU - Mazzola, Laure

AU - Gay, Claire

AU - Stephan, Jean Louis

AU - Milisavljevic, Baptiste

AU - Boucherit, Soraya

AU - Rozenberg, Flore

AU - de Diego, Rebeca Perez

AU - Dix, Richard D.

AU - Marr, Nico

AU - Béziat, Vivien

AU - Cobat, Aurelie

AU - Aubart, Mélodie

AU - Abel, Laurent

AU - Chabrier, Stephane

AU - Smith, Gregory A.

AU - Notarangelo, Luigi D.

AU - Mocarski, Edward S.

AU - Studer, Lorenz

AU - Casanova, Jean Laurent

AU - Zhang, Shen Ying

PY - 2023/4

Y1 - 2023/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85153543944&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85153543944&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.ade2860

DO - 10.1126/sciimmunol.ade2860

M3 - Article

C2 - 37083451

AN - SCOPUS:85153543944

SN - 2470-9468

VL - 8

JO - Science Immunology

JF - Science Immunology

IS - 82

M1 - eade2860

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this