Abstract

Immunological control of viral infection in the brain is essential for immediate protection, but also for long-term maintenance of brain integrity. As the primary resident immune cell of the brain, microglia protect against viral infections through key macrophage functions, including release of the antiviral type I interferons (IFN-I) and clearance of infected cells. Microglia express the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), which can bind viral DNA leading to signaling through stimulator of interferon genes (STING), and downstream immune activation. Here we report that herpes simplex virus (HSV) 1 infection of microglia leads to activation of IFN-I genes and pro-inflammatory cytokines. However, HSV1 also down-regulated expression of a subset of genes, including genes in the pathway engaged by the microglial receptor triggering receptor expressed on myeloid cells-2 (TREM2). Knockdown experiments revealed that TREM2 is important for viral activation of cGAS-STING signaling in microglia, induction of IFN-I, and phagocytosis of HSV1 infected neurons. Consequently, TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron co-cultures and mice in vivo. Mechanistically, we show that TREM2 is essential for phosphorylation of STING, and downstream activation of the IFN-inducing transcription factor IRF3. We conclude that TREM2 is a novel component of the antiviral immune response in microglia, crucial for immediate host defense against HSV1 in the brain. Since both TREM2 loss-of-function mutations and HSV1 serological status are linked to development of Alzheime[r]s disease (AD), this work opens the question whether defects in TREM2 could predispose to impaired viral clearance and post-infection pathological neurological changes.