Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency,Science Immunology

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Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency
Science Immunology ( IF 24.8 ) Pub Date : 2023-04-21 , DOI: 10.1126/sciimmunol.ade2860
Zhiyong Liu ₁ , Eduardo J Garcia Reino ₁ , Oliver Harschnitz _{2,

3} , Hongyan Guo _{4,

5,

6} , Yi-Hao Chan ₁ , Noopur V Khobrekar ₂ , Mary L Hasek ₁ , Kerry Dobbs ₇ , Darawan Rinchai ₁ , Marie Materna _{8,

9} , Daniela Matuozzo _{8,

9} , Danyel Lee _{1,

8,

9} , Paul Bastard _{1,

8,

9,

10} , Jie Chen ₁ , Yoon Seung Lee ₁ , Seong K Kim ₅ , Shuxiang Zhao ₁ , Param Amin ₂ , Lazaro Lorenzo _{8,

9} , Yoann Seeleuthner _{8,

9} , Remi Chevalier _{8,

9} , Laure Mazzola ₁₁ , Claire Gay ₁₁ , Jean-Louis Stephan ₁₁ , Baptiste Milisavljevic ₁ , Soraya Boucherit _{8,

9} , Flore Rozenberg ₁₂ , Rebeca Perez de Diego _{13,

14,

15} , Richard D Dix _{16,

17} , Nico Marr _{18,

19,

20} , Vivien Béziat _{1,

8,

9} , Aurelie Cobat _{1,

8,

9} , Mélodie Aubart _{8,

21} , Laurent Abel _{1,

8,

9} , Stephane Chabrier ₁₁ , Gregory A Smith ₂₂ , Luigi D Notarangelo ₇ , Edward S Mocarski ₄ , Lorenz Studer ₂ , Jean-Laurent Casanova _{1,

8,

9,

23,

24} , Shen-Ying Zhang _{1,

8,

9}

Affiliation

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.
Human Technopole, Viale Rita Levi-Montalcini, Milan, Italy.
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, GA, USA.
School of Medicine, Atlanta, GA, USA.
Louisiana State University Health Sciences Center at Shreveport (LSUHSC-S), Shreveport, LA, USA.
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
Paris City University, Imagine Institute, Paris, France.
Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
Department of Pediatrics, Hôpital Nord, Saint-Etienne, Paris, France.
Laboratory of Virology, Assistance Publique-Hôpitaux de Paris (AP-HP), Cochin Hospital, Paris, France.
Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.
Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.
Interdepartmental Group of Immunodeficiencies, Madrid, Spain.
Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, GA, USA.
Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA.
Research Branch, Sidra Medicine, Doha, Qatar.
Institute of Translational Immunology, Brandenburg Medical School, Brandenburg an der Havel, Germany.
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Pediatric Neurology Department, Necker Hospital for Sick Children, APHP, Paris City University, Paris, France.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
Howard Hughes Medical Institute, New York, NY, USA.

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/DAI-mediated 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-β 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.

中文翻译：

人类遗传性 RIPK3 缺陷中单纯疱疹病毒的脑炎和神经元死亡介导的控制不良

由于不受控制的病毒生长和随后的细胞死亡，皮质神经元中 TLR3 依赖性 I 型 IFN 免疫的先天性错误是前脑单纯疱疹病毒 1 (HSV-1) 脑炎 (HSE) 的基础。我们报告了一名健康的 HSE 患者，其为无义 (R422*) 和移码 (P493fs9*) 复合杂合子RIPK3变种。受体相互作用蛋白激酶 3 (RIPK3) 是一种普遍存在的细胞质激酶，调节细胞死亡结果，包括细胞凋亡和坏死性凋亡。在体外，R422* 和 P493fs9* RIPK3 蛋白会损害 TLR3、TLR4 或 TNFR1 刺激下的细胞凋亡和坏死性凋亡，以及 HSV-1 感染后 ZBP1/DAI 介导的坏死性细胞死亡。患者的成纤维细胞未检测到 RIPK3 表达。TNFR1或TLR3刺激后，患者的细胞没有发生凋亡或坏死性凋亡。HSV-1 感染后，尽管正常诱导抗病毒 IFN-β 和 IFN 刺激基因 (ISG)，但细胞仍支持病毒过度生长。然而，通过应用外源 I 型干扰素，这种表型得到了挽救。患者的人类多能干细胞 (hPSC) 来源的皮质神经元在 HSV-1 感染后表现出细胞死亡受损和病毒生长增强，同基因 RIPK3 敲除的 hPSC 来源的皮质神经元也是如此。因此，遗传性 RIPK3 缺陷会损害皮质神经元中 HSV-1 的细胞死亡依赖性控制，但不会损害 I 型 IFN 的产生或反应，从而导致 HSE 的易感性。

更新日期：2023-04-21

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