Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Nat Immunol. 2018 Oct;19(10):1071-1082. doi: 10.1038/s41590-018-0203-2. Epub 2018 Sep 10.
TLR3 is a sensor of double-stranded RNA that is indispensable for defense against infection with herpes simplex virus type 1 (HSV-1) in the brain. We found here that TLR3 was required for innate immune responses to HSV-1 in neurons and astrocytes. During infection with HSV-1, TLR3 recruited the metabolic checkpoint kinase complex mTORC2, which led to the induction of chemokines and trafficking of TLR3 to the cell periphery. Such trafficking enabled the activation of molecules (including mTORC1) required for the induction of type I interferons. Intracranial infection of mice with HSV-1 was exacerbated by impairment of TLR3 responses with an inhibitor of mTOR and was significantly 'rescued' by potentiation of TLR3 responses with an agonistic antibody to TLR3. These results suggest that the TLR3-mTORC2 axis might be a therapeutic target through which to combat herpes simplex encephalitis.
TLR3 是双链 RNA 的传感器，对于抵抗单纯疱疹病毒 1 型（HSV-1）在大脑中的感染是必不可少的。我们在这里发现，TLR3 对于神经元和星形胶质细胞中对 HSV-1 的先天免疫反应是必需的。在 HSV-1 感染期间，TLR3 募集代谢检查点激酶复合物 mTORC2，这导致趋化因子的诱导和 TLR3 向细胞外周的运输。这种运输使激活分子（包括 mTORC1）所需的诱导 I 型干扰素成为可能。用 mTOR 的抑制剂损害 TLR3 反应会加剧 HSV-1 对小鼠的颅内感染，并且用 TLR3 的激动性抗体增强 TLR3 反应可显著“挽救”这种感染。这些结果表明，TLR3-mTORC2 轴可能是通过对抗单纯疱疹脑炎的治疗靶点。
