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: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Helsinki One Health (HOH)
University of Helsinki, Medicum
University of Helsinki, HUS Inflammation Center
University of Helsinki, HUSLAB
University of Helsinki, Children's Hospital
Date: 2020-11
Language: eng
Number of pages: 7
Belongs to series: Journal of Clinical Immunology
ISSN: 0271-9142
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
hantavirus
central nervous system infections
encephalitis
primary immunodeficiency diseases
genetic diseases
PUUMALA VIRUS-INFECTION
HEMORRHAGIC-FEVER
DEFICIENCY
HYPOPITUITARISM
EXPRESSION
RNA
3121 General medicine, internal medicine and other clinical medicine
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