Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

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.

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection

“…Alexeyev et al reported cases of meningism, epileptic seizures, urinary bladder paralysis, and cerebral hemorrhage in their NE patient cohort [10]. Seizures, confusion, somnolence, and vision loss, mainly among young male patients, have also been reported [8,13,14]. These reports highlight the potential of the acute NE to cause serious and possibly irreversible CNS complications.…”

“…Acute NE may rarely present symptoms and findings consistent with viral encephalitis criteria such as altered mental status or generalized seizures [15]. Moreover, abnormalities of brain parenchyma on neuroimaging and on electroencephalography have been reported [8,10,13,14]. Based on personal unpublished clinical experience, most NE encephalitis patients recover well without long-term sequelae.…”

“…Based on personal unpublished clinical experience, most NE encephalitis patients recover well without long-term sequelae. Cases of permanent disability related to CNS symptoms, however, have been described [8].…”

“…These associated symptoms, together with acute kidney injury (AKI), oliguria, hematuria, proteinuria, and thrombocytopenia, often lead to a precise preliminary diagnosis even before the serological test results are available. While most ocular and CNSrelated symptoms are reversible, serious complications such as pituitary hemorrhage and encephalitis have been reported [5][6][7][8]. Progress in understanding the clinical and biological features of blurred vision and hantavirus CNS involvement has been made recently.…”

Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation

“…TLR3 p.L742F variant is in vitro severely hypomorphic based on experiments on TLR3-deficient P2.1 fibrosarcoma cell line, and the production of IFN-λ and interleukin-6 in response to TLR3 activation by poly(I:C) stimulation was impaired in previously tested SV40 immortalized human skin fibroblasts heterozygous for this variation. 6 She was also found to be positive for TRF1-interacting nuclear factor 2 ( TINF2 ) variant p.Y312* (rs201677741) previously associated with Ewing sarcoma. Pathogenic TINF variants are associated with autosomal dominant dyskeratosis congenita and pathologic telomere lengths (OMIM 604319).…”