Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.

Autor: Partanen T; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland., Chen J; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA., Lehtonen J; Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.; The Folkhälsan Research Center and Medicum, University of Helsinki, Helsinki, Finland., Kuismin O; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland., Rusanen H; Department of Neurology, Oulu University Hospital, Oulu, Finland., Vapalahti O; Department of Virology, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland., Vaheri A; Department of Virology, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland., Anttila VJ; Department of Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland., Bode M; Department of Diagnostic Radiology, Oulu University Hospital and University of Oulu, Oulu, Finland., Hautala N; Department of Ophthalmology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland., Vuorinen T; Department of Medical Microbiology, Institute of Biomedicine, Turku University Hospital and University of Turku, Turku, Finland., Glumoff V; Research Unit of Biomedicine, University of Oulu, Oulu, Finland., Kraatari M; Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland., Åström P; Research Unit of Biomedicine, University of Oulu, Oulu, Finland., Saarela J; Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.; Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway., Kauma H; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland., Lorenzo L; Paris Descartes University, Imagine Institute, 75015, Paris, France., Casanova JL; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA.; Paris Descartes University, Imagine Institute, 75015, Paris, France.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015, Paris, France.; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015, Paris, France.; Howard Hughes Medical Institute, New York, NY, 10065, USA., Zhang SY; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA.; Paris Descartes University, Imagine Institute, 75015, Paris, France.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015, Paris, France., Seppänen M; Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.; Rare Disease Center and Pediatric Research Center, Children and Adolecents, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland., Hautala T; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland. timo.hautala@oulu.fi.; Research Unit of Biomedicine, University of Oulu, Oulu, Finland. timo.hautala@oulu.fi.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2020 Nov; Vol. 40 (8), pp. 1156-1162. Date of Electronic Publication: 2020 Sep 16.
DOI: 10.1007/s10875-020-00834-2
Abstrakt: 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.
Databáze: MEDLINE
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