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Heterozygous TLR3 mutation in patients with hantavirus encephalitis |
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| Author: | Partanen, Terhi1; Chen, Jie2; Lehtonen, Johanna3,4; |
| Organizations: |
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
4The Folkhälsan Research Center and Medicum, University of Helsinki, Helsinki, Finland
5Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland 6Department of Neurology, Oulu University Hospital, Oulu, Finland 7Department of Virology, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland 8Department of Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland 9Department of Diagnostic Radiology, Oulu University Hospital and University of Oulu, Oulu, Finland 10Department of Ophthalmology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland 11Department of Medical Microbiology, Institute of Biomedicine, Turku University Hospital and University of Turku, Turku, Finland 12Research Unit of Biomedicine, University of Oulu, Oulu, Finland 13Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway 14Paris Descartes University, Imagine Institute, 75015, Paris, France 15Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015, Paris, France 16Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015, Paris, France 17Howard Hughes Medical Institute, New York, NY, 10065, USA 18Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland 19Rare Disease Center and Pediatric Research Center, Children and Adolecents, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 0.4 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe202101222345 |
| Language: | English |
| Published: |
Springer Nature,
2020
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| Publish Date: | 2021-01-22 |
| Description: |
AbstractPuumala 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. see all
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| Series: |
Journal of clinical immunology |
| ISSN: | 0271-9142 |
| ISSN-E: | 1573-2592 |
| ISSN-L: | 0271-9142 |
| Volume: | 40 |
| Issue: | 8 |
| Pages: | 1156 - 1162 |
| DOI: | 10.1007/s10875-020-00834-2 |
| OADOI: | https://oadoi.org/10.1007/s10875-020-00834-2 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine 3121 General medicine, internal medicine and other clinical medicine |
| Subjects: | |
| Funding: |
This study was partly supported by Oulu University Hospital VTR, Oulu University MRC, Maud Kuistila Foundation, Finnish Foundation for Pediatric Research and Infektiolääkärit ry. Open access funding provided by University of Oulu including Oulu University Hospital. |
| Copyright information: |
© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
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https://creativecommons.org/licenses/by/4.0/ |