Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis
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ORIGINAL ARTICLE
Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis Terhi Partanen 1 & Jie Chen 2 & Johanna Lehtonen 3,4 & Outi Kuismin 5 & Harri Rusanen 6 & Olli Vapalahti 7 & Antti Vaheri 7 & Veli-Jukka Anttila 8 & Michaela Bode 9 & Nina Hautala 10 & Tytti Vuorinen 11 & Virpi Glumoff 12 & Minna Kraatari 5 & Pirjo Åström 12 & Janna Saarela 3,13 & Heikki Kauma 1 & Lazaro Lorenzo 14 & Jean-Laurent Casanova 2,14,15,16,17 & Shen-Ying Zhang 2,14,15 & Mikko Seppänen 18,19 & Timo Hautala 1,12 Received: 23 May 2020 / Accepted: 20 July 2020 # The Author(s) 2020
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. Keywords Toll-like receptor 3 . hantavirus . central nervous system infections . encephalitis . primary immunodeficiency diseases . genetic diseases
Introduction Zoonotic RNA hantaviruses are carried and spread by rodents. The viruses are shed to rodent urine, droppings, and saliva, and they are mainly transmitted to human by inhalation. Hantaviruses may cause human disease with mortality [1]; hantavirus hemorrhagic fever with renal syndrome (HFRS) occurs in Europe and Asia whereas severe cardiopulmonary syndrome (HCPS) cases are seen in Americas [1, 2]. Puumala hantavirus (PUUV) HFRS is common in Europe with Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-020-00834-2) contains supplementary material, which is available to authorized users. * Timo Hautala [email protected] Extended author information available on the last page of the article
seroprevalence ranging from a few percent to approximately 13% in
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