Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

Springer Science and Business Media LLC - Tập 40 Số 8 - Trang 1156-1162 - 2020
Terhi Partanen1, Jie Chen2, Jussi Lehtonen3, Outi Kuismin4, Harri Rusanen5, Olli Vapalahti6, Antti Vaheri6, Veli‐Jukka Anttila7, Michaela K. Bode8, Nina Hautala9, Tytti Vuorinen10, Virpi Glumoff11, Minna Kraatari4, Pirjo Åström11, Janna Saarela12, Heikki Kauma1, Lazaro Lorenzo13, Jean‐Laurent Casanova13, Shen‐Ying Zhang13, Mikko Seppänen14, Timo Hautala11
1Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
2St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 USA
3Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
4Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
5Department of Neurology, Oulu University Hospital, Oulu, Finland
6Department of Virology, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
7Department of Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
8Department of Diagnostic Radiology, Oulu University Hospital and University of Oulu, Oulu, Finland
9Department of Ophthalmology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
10Department of Medical Microbiology, Institute of Biomedicine, Turku University Hospital and University of Turku, Turku, Finland
11Research Unit of Biomedicine, University of Oulu, Oulu, Finland
12Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway
13Paris Descartes University, Imagine Institute, 75015, Paris, France
14Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland

Tóm tắt

Abstract

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

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Tài liệu tham khảo

Avsic-Zupanc T, Saksida A, Korva M. Hantavirus infections. Clin Microbiol Infect. 2019;21S:e6–e16.

Vaheri A, Henttonen H, Voutilainen L, Mustonen J, Sironen T, Vapalahti O. Hantavirus infections in Europe and their impact on public health. Rev Med Virol. 2013;23:35–49.

Hautala T, Mähonen SM, Sironen T, Hautala N, Pääkkö E, Karttunen A, et al. Central nervous system-related symptoms and findings are common in acute Puumala hantavirus infection. Ann Med. 2010;42:344–51.

Alexeyev OA, Morozov VG. Neurological manifestations of hemorrhagic fever with renal syndrome caused by Puumala virus: review of 811 cases. Clin Infect Dis. 1995;20:255–8.

Hautala T, Sironen T, Vapalahti O, Pääkko E, Särkioja T, Salmela PI, et al. Hypophyseal hemorrhage and panhypopituitarism during Puumala virus infection: magnetic resonance imaging and detection of viral antigen in the hypophysis. Clin Infect Dis. 2002;35:96–101.

Pekic S, Cvijovic G, Stojanovic M, Kendereski A, Micic D, Popovic V. Hypopituitarism as a late complication of hemorrhagic fever. Endocrine. 2005;26:79–82.

Stojanovic M, Pekic S, Cvijovic G, Miljic D, Doknic M, Nikolic-Djurovic M, et al. High risk of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome. J Clin Endocrinol Metab. 2008;93:2722–8.

Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57:1114–28.

Bergmann F, Krone B, Bleich S, Prange H, Paulus W. Encephalitis due to a hantavirus infection. J Inf Secur. 2002;45:58–9.

Krause R, Aberle S, Haberl R, Daxbock F, Wenisch C. Puumala virus infection with acute disseminated encephalomyelitis and multiorgan failure. Emerg Infect Dis. 2003;9:603–5.

Mähönen SM, Sironen T, Vapalahti O, Pääkkö E, Hautala N, Ilonen J, et al. Puumala virus RNA in cerebrospinal fluid in a patient with uncomplicated nephropathia epidemica. J Clin Virol. 2007;40:248–51.

Cerar D, vsic-Zupanc T, Jereb M, Strle F. Case report: severe neurological manifestation of Dobrava hantavirus infection. J Med Virol. 2007;79:1841–3.

Huisa BN, Chapin JE, Adair JC. Central nervous system complications following Hanta virus cardiopulmonary syndrome. J Neuro-Oncol. 2009;15:202–5.

Talamonti L, Padula PJ, Canteli MS, Posner F, Marczeski FP, Weller C. Hantavirus pulmonary syndrome: encephalitis caused by virus Andes. J Neuro-Oncol. 2011;17:189–92.

Fernando R, Capone D, Elrich S, Mantovani R, Quarles L III, D'Amato A, et al. Infection with New York orthohantavirus and associated respiratory failure and multiple cerebral complications. Emerg Infect Dis. 2019;25:1241–3.

Hautala T, Hautala N, Mähonen SM, Sironen T, Pääkko E, Karttunen A, et al. Young male patients are at elevated risk of developing serious central nervous system complications during acute Puumala hantavirus infection. BMC Infect Dis. 2011;11:217.

Lim HK, Seppänen M, Hautala T, Ciancanelli MJ, Itan Y, Lafaille FG, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83:1888–97.

Lim HK, Huang SXL, Chen J, Kerner G, Gilliaux O, Bastard P, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216:2038–56.

Sironi M, Peri AM, Cagliani R, Forni D, Riva S, Biasin M, et al. TLR3 mutations in adult patients with herpes simplex virus and varicella-zoster virus encephalitis. J Infect Dis. 2017;215:1430–4.

Zhang SY, Herman M, Ciancanelli MJ, de Perez DR, Sancho-Shimizu V, Abel L, et al. TLR3 immunity to infection in mice and humans. Curr Opin Immunol. 2013;25:19–33.

Sulonen AM, Ellonen P, Almusa H, Lepistö M, Eldfors S, Hannula S, et al. Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol. 2011;12:R94.

Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.

Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100:267–80.

Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–94.

Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010;6:e1001025.

Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.

Ranjith-Kumar CT, Miller W, Sun J, Xiong J, Santos J, Yarbrough I, et al. Effects of single nucleotide polymorphisms on Toll-like receptor 3 activity and expression in cultured cells. J Biol Chem. 2007;282:17696–705.

Willmann O, Ahmad-Nejad P, Neumaier M, Hennerici MG, Fatar M. Toll-like receptor 3 immune deficiency may be causative for HSV-2-associated mollaret meningitis. Eur Neurol. 2010;63:249–51.

Yang CA, Raftery MJ, Hamann L, Guerreiro M, Grutz G, Haase D, et al. Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. Hum Immunol. 2012;73:844–51.

Cooke G, Kamal I, Strengert M, Hams E, Mawhinney L, Tynan A, et al. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. QJM. 2018;111:217–24.

Gosu V, Son S, Shin D, Song KD. Insights into the dynamic nature of the dsRNA-bound TLR3 complex. Sci Rep. 2019;9:3652.

Sun Y, Leaman DW. Ectopic expression of toll-like receptor-3 (TLR-3) overcomes the double-stranded RNA (dsRNA) signaling defects of P2.1 cells. J Interferon Cytokine Res. 2004;24:350–61.

Guo Y, Audry M, Ciancanelli M, Alsina L, Azevedo J, Herman M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208:2083–98.

Handke W, Oelschlegel R, Franke R, Kruger DH. Rang A Hantaan virus triggers TLR3-dependent innate immune responses. J Immunol. 2009;182:2849–58.

Zhang Y, Liu B, Ma Y, Yi J, Zhang C, Zhang Y, et al. Hantaan virus infection induces CXCL10 expression through TLR3, RIG-I, and MDA-5 pathways correlated with the disease severity. Mediat Inflamm. 2014;2014:697837.

Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, et al. Exome and genome sequencing for inborn errors of immunity. J Allergy Clin Immunol. 2016;138:957–69.

Resman RK, Korva M, Bogovic P, Pal E, Strle F, Avsic-Zupanc T. Delayed interferon type 1-induced antiviral state is a potential factor for hemorrhagic fever with renal syndrome severity. J Infect Dis. 2018;217:926–32.

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Springer Science and Business Media LLC

Tập 40 Số 8

1156-1162

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