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Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity


Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/β immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.

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  1. Abel L, Plancoulaine S, Jouanguy E, Zhang SY, Mahfoufi N, Nicolas N, Sancho-Shimizu V, Alcais A, Guo Y, Cardon A, Boucherit S, Obach D, Clozel T, Lorenzo L, Amsallem D, Berquin P, Blanc T, Bost-Bru C, Chabrier S, Chabrol B, Cheuret E, Dulac O, Evrard P, Heron B, Lazaro L, Mancini J, Pedespan JM, Rivier F, Vallee L, Lebon P, Rozenberg F, Casanova JL, Tardieu M (2010) Age-dependent mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood. J Pediatr 157:623–629.

  2. Alcais A, Quintana-Murci L, Thaler DS, Schurr E, Abel L, Casanova JL (2010) Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?. Ann N Y Acad Sci 1214:18–33.

  3. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738

  4. Andersen LL, Mork N, Reinert LS, Kofod-Olsen E, Narita R, Jorgensen SE, Skipper KA, Honing K, Gad HH, Ostergaard L, Orntoft TF, Hornung V, Paludan SR, Mikkelsen JG, Fujita T, Christiansen M, Hartmann R, Mogensen TH (2015) Functional IRF3 deficiency in a patient with herpes simplex encephalitis. J Exp Med 212:1371–1379.

  5. Arenas J, Hurwitz J (1987) Purification of a RNA debranching activity from HeLa cells. J Biol Chem 262:4274–4279

  6. Armangue T, Baucells BJ, Vlagea A, Petit-Pedrol M, Esteve-Sole A, Deya-Martinez A, Ruiz-Garcia R, Juan M, Perez de Diego R, Dalmau J, Alsina L (2019) Toll-like receptor 3 deficiency in autoimmune encephalitis post-herpes simplex encephalitis. Neurol Neuroimmunol Neuroinflamm 6:e611.

  7. Audry M, Ciancanelli M, Yang K, Cobat A, Chang HH, Sancho-Shimizu V, Lorenzo L, Niehues T, Reichenbach J, Li XX, Israel A, Abel L, Casanova JL, Zhang SY, Jouanguy E, Puel A (2011) NEMO is a key component of NF-kappaB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus. J Allergy Clin Immunol 128:610–617.

  8. Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK, Bouchier C, Tichit M, Neyrolles O, Gicquel B, Kidd JR, Kidd KK, Alcais A, Ragimbeau J, Pellegrini S, Abel L, Casanova JL, Quintana-Murci L (2009) Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet 5:e1000562.

  9. Campbell M, Klapper PE, Longson M (1982) Acyclovir in herpes encephalitis. Lancet 1:38

  10. Casanova JL (2015a) Human genetic basis of interindividual variability in the course of infection. Proc Natl Acad Sci USA 112:E7118–E7127.

  11. Casanova JL (2015b) Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc Natl Acad Sci USA 112:E7128–E7137.

  12. Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A, Yang K, Alcais A, Picard C, Mahfoufi N, Nicolas N, Lorenzo L, Plancoulaine S, Senechal B, Geissmann F, Tabeta K, Hoebe K, Du X, Miller RL, Heron B, Mignot C, de Villemeur TB, Lebon P, Dulac O, Rozenberg F, Beutler B, Tardieu M, Abel L, Casanova JL (2006) Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314:308–312

  13. Chapgier A, Wynn RF, Jouanguy E, Filipe-Santos O, Zhang S, Feinberg J, Hawkins K, Casanova JL, Arkwright PD (2006) Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J Immunol 176:5078–5083

  14. Chapgier A, Kong XF, Boisson-Dupuis S, Jouanguy E, Averbuch D, Feinberg J, Zhang SY, Bustamante J, Vogt G, Lejeune J, Mayola E, de Beaucoudrey L, Abel L, Engelhard D, Casanova JL (2009) A partial form of recessive STAT1 deficiency in humans. J Clin Invest 119:1502–1514.

  15. Chapman KB, Boeke JD (1991) Isolation and characterization of the gene encoding yeast debranching enzyme. Cell 65:483–492

  16. Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, Al-Jumaah S, Yang K, Chapgier A, Eidenschenk C, Eid P, Al Ghonaium A, Tufenkeji H, Frayha H, Al-Gazlan S, Al-Rayes H, Schreiber RD, Gresser I, Casanova JL (2003) Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33:388–391

  17. Galvis AE, Fisher HE, Fan H, Camerini D (2017) Conformational changes in the 5′ end of the HIV-1 genome dependent on the debranching enzyme DBR1 during early stages of infection. J Virol.

  18. Garcia-Morato B, Apalategi CA, Bravo-Galego L, Blaquez Moreno A, Soimon-Fuentes M, Garmendia J, Mendez Echevarria A, Del Rosal RT, Dominguez-Solo A, Lopez-Granados E, Reyburn H, Roriguez Pena R (2019) Impaired control of multiple viral infections in a family with complete IRF9 deficiency. J Allergy Clin Immunol 144:309–312

  19. Gazquez I, Jover A, Puig T, Vincente de Vera C, Rubio M (1996) Familial herpes encephalitis. Lancet 347:910

  20. Gnann JW Jr, Whitley RJ (2017) Herpes simplex encephalitis: an update. Curr Infect Dis Rep 19:13.

  21. Guo Y, Audry M, Ciancanelli M, Alsina L, Azevedo J, Herman M, Anguiano E, Sancho-Shimizu V, Lorenzo L, Pauwels E, Philippe PB, Perez de Diego R, Cardon A, Vogt G, Picard C, Andrianirina ZZ, Rozenberg F, Lebon P, Plancoulaine S, Tardieu M, Valerie D, Jouanguy E, Chaussabel D, Geissmann F, Abel L, Casanova JL, Zhang SY (2011) Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med 208:2083–2098.

  22. Han B, Park HK, Ching T, Panneerselvam J, Wang H, Shen Y, Zhang J, Li L, Che R, Garmire L, Fei P (2017) Human DBR1 modulates the recycling of snRNPs to affect alternative RNA splicing and contributes to the suppression of cancer development. Oncogene.

  23. Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E, Sancho-Shimizu V, Perez de Diego R, Abhyankar A, Israelsson E, Guo Y, Cardon A, Rozenberg F, Lebon P, Tardieu M, Heropolitanska-Pliszka E, Chaussabel D, White MA, Abel L, Zhang SY, Casanova JL (2012) Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med.

  24. Hjalmarsson A, Blomqvist P, Skoldenberg B (2007) Herpes simplex encephalitis in Sweden, 1990–2001: incidence, morbidity, and mortality. Clin Infect Dis 45:875–880

  25. Jackson AC, Melanson M, Rossiter JP (2002) Familial herpes simplex encephalitis. Ann Neurol 51:406–407

  26. Jacquier A, Rosbash M (1986) RNA splicing and intron turnover are greatly diminished by a mutant yeast branch point. Proc Natl Acad Sci USA 83:5835–5839

  27. Jorjani H, Kehr S, Jedlinski DJ, Gumienny R, Hertel J, Stadler PF, Zavolan M, Gruber AR (2016) An updated human snoRNAome. Nucleic Acids Res 44:5068–5082.

  28. Jubelt B, Mihai C, Li TM, Veerapaneni P (2011) Rhombencephalitis/brainstem encephalitis. Curr Neurol Neurosci Rep 11:543–552.

  29. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825.

  30. Kelly D, Kroll JS (2004) Encephalitis–beyond aciclovir. Adv Exp Med Biol 549:177–183

  31. Kiss AM (2004) Human box H/ACA pseudouridylation guide RNA machinery. Mol Cell Biol 24:11

  32. Kohl S (1988) Herpes simplex virus encephalitis in children. Pediatr Clin North Am 35:465–483

  33. Kohl S (1998) Herpes simplex virus. In: Feigin RD, Cherry JD (eds) Textbook of pediatric infectious diseases, vol 2, 4th edn. W.B. Saunders, Philadelphia, pp 1703–1732

  34. Koskiniemi M, Saarinen A, Klapper PE, Sarna S, Cleator G, Vaheri A (1995) Familial herpes encephalitis. Lancet 346:1553

  35. Lafaille FG, Pessach IM, Zhang SY, Ciancanelli MJ, Herman M, Abhyankar A, Ying SW, Keros S, Goldstein PA, Mostoslavsky G, Ordovas-Montanes J, Jouanguy E, Plancoulaine S, Tu E, Elkabetz Y, Al-Muhsen S, Tardieu M, Schlaeger TM, Daley GQ, Abel L, Casanova JL, Studer L, Notarangelo LD (2012) Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491:769–773.

  36. Lafaille FG, Harschnitz O, Lee YS, Zhang P, Hasek ML, Kerner G, Itan Y, Ewaleifoh O, Rapaport F, Carlile TM, Carter-Timofte ME, Paquet D, Dobbs K, Zimmer B, Gao D, Rojas-Duran MF, Kwart D, Rattina V, Ciancanelli MJ, McAlpine JL, Lorenzo L, Boucherit S, Rozenberg F, Halwani R, Henry B, Amenzoui N, Alsum Z, Marques L, Church JA, Al-Muhsen S, Tardieu M, Bousfiha AA, Paludan SR, Mogensen TH, Quintana-Murci L, Tessier-Lavigne M, Smith GA, Notarangelo LD, Studer L, Gilbert W, Abel L, Casanova JL, Zhang SY (2019) Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nat Med 25:1873–1884.

  37. Lerner AM, Levine DP, Reyes MP (1983) Two cases of herpes simplex virus encephalitis in the same family. N Engl J Med 308:1481

  38. Liang F, Glans H, Enoksson SL, Kolios AGA, Lore K, Nilsson J (2019) Recurrent herpes zoster ophthalmicus in a patient with a novel toll-like receptor 3 variant linked to compromised activation capacity in fibroblasts. J Infect Dis.

  39. Lim HK, Seppanen M, Hautala T, Ciancanelli MJ, Itan Y, Lafaille FG, Dell W, Lorenzo L, Byun M, Pauwels E, Ronnelid Y, Cai X, Boucherit S, Jouanguy E, Paetau A, Lebon P, Rozenberg F, Tardieu M, Abel L, Yildiran A, Vergison A, Roivainen R, Etzioni A, Tienari PJ, Casanova JL, Zhang SY (2014) TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology 83:1888–1897.

  40. Lim HK, Huang SXL, Chen J, Kerner G, Gilliaux O, Bastard P, Dobbs K, Hernandez N, Goudin N, Hasek ML, Garcia Reino EJ, Lafaille FG, Lorenzo L, Luthra P, Kochetkov T, Bigio B, Boucherit S, Rozenberg F, Vedrinne C, Keller MD, Itan Y, Garcia-Sastre A, Celard M, Orange JS, Ciancanelli MJ, Meyts I, Zhang Q, Abel L, Notarangelo LD, Snoeck HW, Casanova JL, Zhang SY (2019) Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med 216(9):2038–2056.

  41. Mikami T, Miyashita H, Takatsuka S, Kuroki Y, Matsushima N (2012) Molecular evolution of vertebrate Toll-like receptors: evolutionary rate difference between their leucine-rich repeats and their TIR domains. Gene 503:235–243.

  42. Mork N, Kofod-Olsen E, Sorensen KB, Bach E, Orntoft TF, Ostergaard L, Paludan SR, Christiansen M, Mogensen TH (2015) Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun 16:552–566.

  43. Murray JL, Sheng J, Rubin DH (2014) A role for H/ACA and C/D small nucleolar RNAs in viral replication. Mol Biotechnol 56:429–437.

  44. Nam K, Hudson RH, Chapman KB, Ganeshan K, Damha MJ, Boeke JD (1994) Yeast lariat debranching enzyme. Substrate and sequence specificity. J Biol Chem 269:20613–20621

  45. Nam K, Lee G, Trambley J, Devine SE, Boeke JD (1997) Severe growth defect in a Schizosaccharomyces pombe mutant defective in intron lariat degradation. Mol Cell Biol 17:809–818

  46. Niehues T, Reichenbach J, Neubert J, Gudowius S, Puel A, Horneff G, Lainka E, Dirksen U, Schroten H, Döffinger R, Casanova JL, Wahn V (2004) A NEMO-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J Allergy Clin Immunol 114:1456–1462

  47. Notarangelo L, Casanova JL, Conley ME, Chapel H, Fischer A, Puck J, Roifman C, Seger R, Geha RS (2006) Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol 117:883–896

  48. Ochs H, Smith CIE, Puck J (2007) Primary Immunodeficiencies: a molecular and genetic approach, 2nd edn. Oxford University Press, New York

  49. Ogunjimi B, Zhang SY, Sorensen KB, Skipper KA, Carter-Timofte M, Kerner G, Luecke S, Prabakaran T, Cai Y, Meester J, Bartholomeus E, Bolar NA, Vandeweyer G, Claes C, Sillis Y, Lorenzo L, Fiorenza RA, Boucherit S, Dielman C, Heynderickx S, Elias G, Kurotova A, Auwera AV, Verstraete L, Lagae L, Verhelst H, Jansen A, Ramet J, Suls A, Smits E, Ceulemans B, Van Laer L, Plat Wilson G, Kreth J, Picard C, Von Bernuth H, Fluss J, Chabrier S, Abel L, Mortier G, Fribourg S, Mikkelsen JG, Casanova JL, Paludan SR, Mogensen TH (2017) Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections. J Clin Invest 127:3543–3556.

  50. Ooi SL, Samarsky DA, Fournier MJ, Boeke JD (1998) Intronic snoRNA biosynthesis in Saccharomyces cerevisiae depends on the lariat-debranching enzyme: intron length effects and activity of a precursor snoRNA. RNA 4:1096–1110

  51. Perez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C, Herman M, Cardon A, Durandy A, Bustamante J, Vallabhapurapu S, Bravo J, Warnatz K, Chaix Y, Cascarrigny F, Lebon P, Rozenberg F, Karin M, Tardieu M, Al-Muhsen S, Jouanguy E, Zhang SY, Abel L, Casanova JL (2010) Human TRAF3 adaptor molecule deficiency leads to impaired toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33:400–411.

  52. Perng GC, Jones C (2010) Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle. Interdiscip Perspect Infect Dis 2010:262415.

  53. Petfalski E, Dandekar T, Henry Y, Tollervey D (1998) Processing of the precursors to small nucleolar RNAs and rRNAs requires common components. Mol Cell Biol 18:1181–1189

  54. Plotch SJ, Krug RM (1986) In vitro splicing of influenza viral NS1 mRNA and NS1-beta-globin chimeras: possible mechanisms for the control of viral mRNA splicing. Proc Natl Acad Sci USA 83:5444–5448

  55. Puel A, Reichenbach J, Bustamante J, Ku CL, Feinberg J, Doffinger R, Bonnet M, Filipe-Santos O, Beaucoudrey L, Durandy A, Horneff G, Novelli F, Wahn V, Smahi A, Israel A, Niehues T, Casanova JL (2006) The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation. Am J Hum Genet 78:691–701

  56. Raschilas F, Wolff M, Delatour F, Chaffaut C, De Broucker T, Chevret S, Lebon P, Canton P, Rozenberg F (2002) Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 35:254–260

  57. Reinert LS, Harder L, Holm CK, Iversen MB, Horan KA, Dagnaes-Hansen F, Ulhoi BP, Holm TH, Mogensen TH, Owens T, Nyengaard JR, Thomsen AR, Paludan SR (2012) TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. J Clin Invest 122:1368–1376.

  58. Reinert LS, Lopusna K, Winther H, Sun C, Thomsen MK, Nandakumar R, Mogensen TH, Meyer M, Vaegter C, Nyengaard JR, Fitzgerald KA, Paludan SR (2016) Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS. Nat Commun 7:13348.

  59. Ruskin B, Green MR (1985) An RNA processing activity that debranches RNA lariats. Science 229:135–140

  60. Sancho-Shimizu V, Perez de Diego R, Lorenzo L, Halwani R, Alangari A, Israelsson E, Fabrega S, Cardon A, Maluenda J, Tatematsu M, Mahvelati F, Herman M, Ciancanelli M, Guo Y, Alsum Z, Alkhamis N, Al-Makadma AS, Ghadiri A, Boucherit S, Plancoulaine S, Picard C, Rozenberg F, Tardieu M, Lebon P, Jouanguy E, Rezaei N, Seya T, Matsumoto M, Chaussabel D, Puel A, Zhang SY, Abel L, Al-Muhsen S, Casanova JL (2011) Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest 121:4889–4902.

  61. Sato R, Kato A, Chimura T, Saitoh SI, Shibata T, Murakami Y, Fukui R, Liu K, Zhang Y, Arii J, Sun-Wada GH, Wada Y, Ikenoue T, Barber GN, Manabe T, Kawaguchi Y, Miyake K (2018) Combating herpesvirus encephalitis by potentiating a TLR3-mTORC2 axis. Nat Immunol 19:1071–1082.

  62. Schlesinger Y, Buller RS, Brunstrom JE, Moran CJ, Storch GA (1995) Expanded spectrum of herpes simplex encephalitis in childhood. J Pediatr 126:234–241

  63. Sedger LM (2013) microRNA control of interferons and interferon induced anti-viral activity. Mol Immunol 56:781–793.

  64. Sironi M, Peri AM, Cagliani R, Forni D, Riva S, Biasin M, Clerici M, Gori A (2017) TLR3 mutations in adult patients with herpes simplex virus and varicella-zoster virus encephalitis. J Infect Dis 215:1430–1434.

  65. Smith G (2012) Herpesvirus transport to the nervous system and back again. Annu Rev Microbiol 66:153–176.

  66. Smith MG, Lennette EH, Reames HR (1941) Isolation of the virus of herpes simplex and the demonstration of intranuclear inclusions in a case of acute encephalitis. Am J Pathol 17:55–68

  67. Stahl JP, Mailles A (2019) Herpes simplex virus encephalitis update. Curr Opin Infect Dis 32:239–243.

  68. Tangye SG, Al-Herz W, Bousfiha A, Hatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Picard C, Puck J, Torgerson TR, Casanova JL, Sullivan KE (2020) Human inborn errors of immunity: 2019 update on the classification from the international union of immunological societies expert committee. J Clin Immunol.

  69. Ulfendahl PJ, Kreivi JP, Akusjarvi G (1989) Role of the branch site/3′-splice site region in adenovirus-2 E1A pre-mRNA alternative splicing: evidence for 5′- and 3′-splice site co-operation. Nucleic Acids Res 17:925–938

  70. Vitturi BK, Rosemberg S, Arita FN, da Rocha AJ, Forte WCN, Tilbery CP (2019) Multiphasic disseminated encephalomyelitis associated with herpes virus infection in a patient with TLR3 deficiency. Mult Scler Relat Disord 36:101379.

  71. Whitley RJ (2002) Herpes simplex virus in children. Curr Treat Options Neurol 4:231–237

  72. Whitley RJ (2006) Herpes simplex encephalitis: adolescents and adults. Antiviral Res 71:141–148

  73. Whitley RJ (2015) Herpes simplex virus infections of the central nervous system. Continuum 21:1704–1713.

  74. Whitley RJ, Gnann JW (1993) The epidemiology and clinical manifestation of herpes simplex virus infections. In: Roizman RJW, Lopez C (eds) The humanherpesviruses. Raven Press, New York, pp 69–105

  75. Zhang SY, Casanova JL (2015) Inborn errors underlying herpes simplex encephalitis: from TLR3 to IRF3. J Exp Med 212:1342–1343.

  76. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, Lebon P, Heron B, Vallee L, Quintana-Murci L, Hovnanian A, Rozenberg F, Vivier E, Geissmann F, Tardieu M, Abel L, Casanova JL (2007) TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–1527

  77. Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ, Okada S, Mandel H, Garcia P, Ciancanelli MJ, Biran A, Lafaille FG, Tsumura M, Cobat A, Luo J, Volpi S, Zimmer B, Sakata S, Dinis A, Ohara O, Garcia Reino EJ, Dobbs K, Hasek M, Holloway SP, McCammon K, Hussong SA, DeRosa N, Van Skike CE, Katolik A, Lorenzo L, Hyodo M, Faria E, Halwani R, Fukuhara R, Smith GA, Galvan V, Damha MJ, Al-Muhsen S, Itan Y, Boeke JD, Notarangelo LD, Studer L, Kobayashi M, Diogo L, Fairbrother WG, Abel L, Rosenberg BR, Hart PJ, Etzioni A, Casanova JL (2018) Inborn errors of RNA lariat metabolism in humans with brainstem viral infection. Cell 172:952–965.

  78. Zhang SY, Jouanguy E, Zhang Q, Abel L, Puel A, Casanova JL (2019) Human inborn errors of immunity to infection affecting cells other than leukocytes: from the immune system to the whole organism. Curr Opin Immunol 59:88–100.

  79. Zimmer B, Ewaleifoh O, Harschnitz O, Lee YS, Peneau C, McAlpine JL, Liu B, Tchieu J, Steinbeck JA, Lafaille F, Volpi S, Notarangelo LD, Casanova JL, Zhang SY, Smith GA, Studer L (2018) Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection. Proc Natl Acad Sci USA 115:E8775–E8782.

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I thank Jean-Laurent Casanova for critical reading of this manuscript. I thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions, and technical and administrative assistance. I would also like to thank the patients and their families for participating in our studies. Our work on the human genetics of herpes simplex encephalitis was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program (UL1TR001866), NIH (R21NS084255, R01AI088364 and R01NS072381), the French National Research Agency (ANR) (ANR-14-CE14-0008-01, AAPG2018-SEAeHostFactors, AAPG2019-CNSVIRGEN and ANR-10-LABX-62-IBEID), the Thrasher Research Fund, the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St Giles Foundation.

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Zhang, S. Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity. Hum Genet (2020).

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