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

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 IFNB 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 co-cultures and in the mouse brain. TREM2 augmented STING signaling and activation of down-stream targets TBK1 and IRF3. Thus, TREM2 is important for the antiviral immune response in microglia. Since TREM2 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 predisposes to post-infection neurological pathologies. One Sentence Summary We identify TREM2 as an important component of the antiviral immune response in microglia, which is actively targeted by HSV1.