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.

普马拉汉坦病毒 (PUUV) 肾综合征出血热 (HFRS) 在北欧很常见；这种感染通常是自限性的，严重的并发症并不常见。然而，PUUV 和其他汉坦病毒很少引起脑炎。这些罕见和严重事件的发病机制尚不清楚。在这项研究中，我们探讨了先天抗病毒免疫的遗传缺陷，类似于 HSV-1 脑炎中看到的 Toll 样受体 3 (TLR3) 突变，可能解释 PUUV 脑炎的可能性。我们完成了 7 名在急性 PUUV 感染期间患有脑炎或脑脊髓炎的成年患者的外显子组测序。我们在七名无关患者中的两名患者中发现了 TLR3 p.L742F 新变体的杂合性（29%，p = 0.0195）。对来自表达突变型或野生型 TLR3 的患者皮肤的 TLR3 缺陷型 P2.1 纤维肉瘤细胞系和 SV40 永生化成纤维细胞（SV40-成纤维细胞）进行了功能测试。当在 P2.1 细胞中表达时，TLR3 p.L742F 等位基因显示出低聚 (I:C) 刺激的细胞因子诱导。来自三个健康对照的 SV40 成纤维细胞在刺激 24 小时后随着聚 (I:C) 浓度的增加产生增加水平的 IFN-λ 和 IL-6，而细胞因子的产生在 TLR3 L742F/WT 患者 SV40-成纤维细胞。杂合 TLR3 突变可能不仅是 HSV-1 脑炎的基础，也是 PUUV 汉坦病毒脑炎的基础。这种可能性应该在由这些和其他汉坦病毒引起的脑炎中进一步探索。