TREM2 在小胶质细胞中受 HSV1 下调，并参与大脑中的抗病毒防御。

TREM2 is down-regulated by HSV1 in microglia and involved in antiviral defense in the brain.

机构信息

Department of Rheumatology and Inflammatory Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

出版信息

Sci Adv. 2023 Aug 18;9(33):eadf5808. doi: 10.1126/sciadv.adf5808.

Immunological control of viral infections in the brain exerts immediate protection and also long-term maintenance of brain integrity. Microglia are important for antiviral defense in the brain. Here, we report that herpes simplex virus type 1 (HSV1) infection of human induced pluripotent stem cell (hiPSC)-derived microglia down-regulates expression of genes in the TREM2 pathway. TREM2 was found to be important for virus-induced induction through the DNA-sensing cGAS-STING pathway in microglia and for phagocytosis of HSV1-infected neurons. Consequently, TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron cocultures and in the mouse brain. TREM2 augmented STING signaling and activation of downstream targets TBK1 and IRF3. Thus, TREM2 is important for the antiviral immune response in microglia. Since loss-of-function mutations and HSV1 serological status are both linked to Alzheimer's disease, this work poses the question whether genetic or virus-induced alterations of TREM2 activity predispose to post-infection neurological pathologies.

免疫控制病毒感染大脑既能提供即时保护，也能长期维持大脑完整性。小胶质细胞在大脑抗病毒防御中起重要作用。在这里，我们报告单纯疱疹病毒 1 型（HSV1）感染诱导多能干细胞（hiPSC）衍生的小胶质细胞下调 TREM2 途径中的基因表达。发现 TREM2 通过 DNA 感应 cGAS-STING 途径在小胶质细胞中对病毒诱导的诱导和对 HSV1 感染神经元的吞噬作用很重要。因此，TREM2 的耗竭增加了人小胶质细胞-神经元共培养物和小鼠大脑中 HSV1 感染的易感性。TREM2 增强了 STING 信号转导和下游靶标 TBK1 和 IRF3 的激活。因此，TREM2 对小胶质细胞中的抗病毒免疫反应很重要。由于功能丧失突变和 HSV1 血清学状态均与阿尔茨海默病有关，这项工作提出了一个问题，即 TREM2 活性的遗传或病毒诱导改变是否会导致感染后神经病理学。