[en] Varicella-zoster virus (VZV) is a neurotropic member of the Herpesviridae family which causes varicella in primary infection and zoster during reactivation but in rare cases can lead to severe neurological complications, such as encephalitis. To identify inborn errors of immunity (IEI) and unravel pathways involved in VZV CNS immune responses and pathogenesis, we performed whole exome sequencing on a cohort of 38 children with neurological manifestations, including VZV encephalitis, cerebellitis, or stroke. We identified a total of 46 rare potentially pathogenic variants predicted to be deleterious, including variants in innate antiviral immunity, inflammation, cell stress responses, and autophagy. Collectively these findings represent a knowledge base for further functional studies and provide new insights into the genetic landscape of VZV CNS infections and highlight potential genetic defects that may compromise host defense, enabling new avenues for diagnosis and personalized treatment strategies for VZV CNS infections.
Disciplines :
Pediatrics Neurology
Author, co-author :
Winzig, Franziska ; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Center for Immunology for Viral Infections (CiViA), Aarhus University, Aarhus, Denmark
De Keukeleere, Kerstin; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Center for Immunology for Viral Infections (CiViA), Aarhus University, Aarhus, Denmark
Bartholomeus, Esther ; Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium ; Center for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium ; Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium
Deconinck, Nicolas; Department of Paediatric Neurology, Hôpital Universitaire de Bruxelles (HUB ; Hôpital Universitaire des Enfants Reine Fabiola (HUDERF ; Université Libre de Bruxelles, ULB, Brussels, Belgium
Barrea, Christophe ; Université de Liège - ULiège > Département des sciences cliniques > Médecine générale
Matthijs, Inge; Department of Paediatrics, AZ Delta, Roeselare, Belgium
Jansen, Anna C ; Division of Pediatric Neurology, Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium ; Translational Neurosciences, University of Antwerp, Wilrijk, Belgium
Verhelst, Helene ; Department of Pediatrics, Division of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium ; Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
Dielman, Charlotte; Department of Paediatrics, Ziekenhuis Aan de Stroom (ZAS), Antwerp, Belgium
Kuznetsova, Maria ; Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium ; Center for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium ; Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium
Ha, My ; Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium ; Center for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium ; Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium
Suls, Arvid; Center of Medical Genetics, University of Antwerp
van der Sluis, Renee M ; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Center for Immunology for Viral Infections (CiViA), Aarhus University, Aarhus, Denmark
Ogunjimi, Benson; Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium ; Center for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium ; Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium ; Department of Paediatrics, Ziekenhuis Aan de Stroom (ZAS), Antwerp, Belgium ; Department of Paediatrics, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium ; Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium
Mogensen, Trine H ; Department of Biomedicine, Aarhus University, Aarhus, Denmark ; Center for Immunology for Viral Infections (CiViA), Aarhus University, Aarhus, Denmark ; Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Mogensen TH, Larsen CS. Aseptic meningitis caused by reactivation of varicella-zoster virus in two immunocompetent patients. Scand J Infect Dis 2006; 38: 815-8.
Liu L. Fields virology, 6th edition. Clin Infect Dis 2014; 59: 613-.
Carter-Timofte ME, Hansen AF, Mardahl M, et al. Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins. Neurol Neuroimmunol Neuroinflamm 2018; 5: e500.
Herlin LK, Hansen KS, Bodilsen J, et al. Varicella zoster virus encephalitis in Denmark from 2015 to 2019-a nationwide prospective cohort study. Clin Infect Dis 2021; 72: 1192-9.
Heinz JL, Hinke DM, Maimaitili M, et al. Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity. J Med Virol 2024; 96: e29690.
Thomsen MM, Tyrberg T, Skaalum K, et al. Genetic variants and immune responses in a cohort of patients with varicella zoster virus encephalitis. J Infect Dis 2021; 224: 2122-32.
Randall KL, Flesch IEA, Mei Y et al. DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection. J Infect Dis 2024; 230: 721.
Kennedy PG, Mogensen TH. Determinants of neurological syndromes caused by varicella zoster virus (VZV). J Neurovirol 2020; 26: 482-95.
Paludan SR, Mogensen TH. Constitutive and latent immune mechanisms exert 'silent' control of virus infections in the central nervous system. Curr Opin Immunol 2021; 72: 158-66.
Spinner MA, Ker JP, Stoudenmire CJ, et al. GATA2 deficiency underlying severe blastomycosis and fatal herpes simplex virus-Associated hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol 2016; 137: 638-40.
Reyahi A, Studahl M, Skouboe MK, et al. An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis. JCI Insight 2023; 8: e173066.
Dobbs K, Domínguez Conde C, Zhang SY, et al. Inherited DOCK2 deficiency in patients with early-onset invasive infections. N Engl J Med 2015; 372: 2409-22.
Aydin SE, Kilic SS, Aytekin C, et al. DOCK8 deficiency: clinical and immunological phenotype and treatment options-a review of 136 patients. J Clin Immunol 2015; 35: 189-98.
Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol 2014; 26: 454-70.
Jouanguy E, Béziat V, Mogensen TH, Casanova JL, Tangye SG, Zhang SY. Human inborn errors of immunity to herpes viruses. Curr Opin Immunol 2020; 62: 106-22.
Carter-Timofte ME, Paludan SR, Mogensen TH. RNA polymerase III as a gatekeeper to prevent severe VZV infections. Trends Mol Med 2018; 24: 904-15.
Ogunjimi B, Zhang SY, Sørensen KB, et al. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. J Clin Invest 2017; 127: 3543-56.
Carter-Timofte ME, Hansen AF, Christiansen M, Paludan SR, Mogensen TH. Mutations in RNA polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection. Genes Immun 2019; 20: 214-23.
Heinz JL, Swagemakers SMA, von Hofsten J, et al. Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-Associated genetic variants. Front Mol Neurosci 2023; 16: 1253040.
Hait AS, Thomsen MM, Larsen SM, et al. Whole-exome sequencing of patients with recurrent HSV-2 lymphocytic Mollaret meningitis. J Infect Dis 2021; 223: 1776-86.
Tordai H, Torres O, Csepi M, Padányi R, Lukács GL, Hegedűs T. Analysis of AlphaMissense data in different protein groups and structural context. Sci Data 2024; 11: 495.
Naesens L, Haerynck F, Gack MU. The RNA polymerase III-RIG-I axis in antiviral immunity and inflammation. Trends Immunol 2023; 44: 435-49.
Patel RC, Sen GC. PACT, a protein activator of the interferon-induced protein kinase, PKR. Embo J 1998; 17: 4379-90.
Chukwurah E, Farabaugh KT, Guan BJ, Ramakrishnan P, Hatzoglou M. A tale of two proteins: PACT and PKR and their roles in inflammation. Febs J 2021; 288: 6365-91.
Qiao H, Jiang T, Mu P, et al. Cell fate determined by the activation balance between PKR and SPHK1. Cell Death Differ 2021; 28: 401-18.
Mitchell S, Vargas J, Hoffmann A. Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med 2016; 8: 227-41.
Hait AS, Olagnier D, Sancho-Shimizu V, et al. Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans. Sci Immunol 2020; 5: eabc2691.
Ballesteros-Álvarez J, Andersen JK. mTORC2: The other mTOR in autophagy regulation. Aging Cell 2021; 20: e13431.
Sabli IK, Sancho-Shimizu V. Inborn errors of autophagy and infectious diseases. Curr Opin Immunol 2021; 72: 272-6.
Heinz J, Kennedy PGE, Mogensen TH. The role of autophagy in varicella zoster virus infection. Viruses 2021; 13: 1053.
Deretic V, Levine B. Autophagy balances inflammation in innate immunity. Autophagy 2018; 14: 243-51.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069-75.
Hao D, Gao P, Liu P, et al. AC3-33, a novel secretory protein, inhibits Elk1 transcriptional activity via ERK pathway. Mol Biol Rep 2011; 38: 1375-82.
Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal 2019; 12: eaav5183.
Ma X, Dong L, Liu X, Ou K, Yang L. POLE/POLD1 mutation and tumor immunotherapy. J Exp Clin Cancer Res 2022; 41: 216.
Desai D, Dugel PU. Complement cascade inhibition in geographic atrophy: A review. Eye (Lond) 2022; 36: 294-302.
Orvedahl A, Alexander D, Tallóczy Z, et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 2007; 1: 23-35.
Wong J, Zhang J, Si X, et al. Autophagosome supports coxsackievirus B3 replication in host cells. J Virol 2008; 82: 9143-53.
Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 2013; 13: 722-37.
Chen J, Ye C, Wan C, et al. The roles of c-Jun N-Terminal kinase (JNK) in infectious diseases. Int J Mol Sci 2021; 22: 9640.
Rahaus M, Desloges N, Wolff MH. ORF61 protein of varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation. J Med Virol 2005; 76: 424-33.
Zapata HJ, Nakatsugawa M, Moffat JF. Varicella-zoster virus infection of human fibroblast cells activates the c-Jun N-Terminal kinase pathway. J Virol 2007; 81: 977-90.
Kurapati S, Sadaoka T, Rajbhandari L, et al. Role of the JNK pathway in varicella-zoster virus lytic infection and reactivation. J Virol 2017; 91: e00640-17.
