A1 Refereed original research article in a scientific journal
Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis
Authors: Terhi Partanen, Jie Chen, Johanna Lehtonen, Outi Kuismin, Harri Rusanen, Olli Vapalahti, Antti Vaheri, Veli-Jukka Anttila, Michaela Bode, Nina Hautala, Tytti Vuorinen, Virpi Glumoff, Minna Kraatari, Pirjo Åström, Janna Saarela, Heikki Kauma, Lazaro Lorenzo, Jean-Laurent Casanova, Shen-Ying Zhang, Mikko Seppänen, Timo Hautala
Publisher: SPRINGER/PLENUM PUBLISHERS
Publication year: 2020
Journal: Journal of Clinical Immunology
Journal name in source: JOURNAL OF CLINICAL IMMUNOLOGY
Journal acronym: J CLIN IMMUNOL
Volume: 40
Issue: 8
First page : 1156
Last page: 1162
Number of pages: 7
ISSN: 0271-9142
eISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-020-00834-2
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/50468133
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.
Downloadable publication This is an electronic reprint of the original article. |  |
