Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

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Partanen , T , Chen , J , Lehtonen , J , Kuismin , O , Rusanen , H , Vapalahti , O , Vaheri , A , Anttila , V-J , Bode , M , Hautala , N , Vuorinen , T , Glumoff , V , Kraatari , M , Åström , P , Saarela , J , Kauma , H , Lorenzo , L , Casanova , J-L , Zhang , S-Y , Seppänen , M & Hautala , T 2020 , ' Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis ' , Journal of Clinical Immunology , vol. 40 , no. 8 , pp. 1156-1162 . https://doi.org/10.1007/s10875-020-00834-2

Title: Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis
Author: Partanen, Terhi; Chen, Jie; Lehtonen, Johanna; Kuismin, Outi; Rusanen, Harri; Vapalahti, Olli; Vaheri, Antti; Anttila, Veli-Jukka; Bode, Michaela; Hautala, Nina; Vuorinen, Tytti; Glumoff, Virpi; Kraatari, Minna; Åström, Pirjo; Saarela, Janna; Kauma, Heikki; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying; Seppänen, Mikko; Hautala, Timo
Contributor organization: Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
University of Helsinki
Helsinki One Health (HOH)
Veterinary Microbiology and Epidemiology
Veterinary Biosciences
Olli Pekka Vapalahti / Principal Investigator
Viral Zoonosis Research Unit
Department of Virology
Helsinki University Hospital Area
HUS Inflammation Center
Doctoral Programme in Clinical Research
Infektiosairauksien yksikkö
Janna Saarela / Principal Investigator
Children's Hospital
HUS Children and Adolescents
Department of Medicine
Date: 2020-11
Language: eng
Number of pages: 7
Belongs to series: Journal of Clinical Immunology
ISSN: 0271-9142
DOI: https://doi.org/10.1007/s10875-020-00834-2
URI: http://hdl.handle.net/10138/320833
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-lambda 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.
Subject: Toll-like receptor 3
central nervous system infections
primary immunodeficiency diseases
genetic diseases
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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