EGR Proteins Mediate Interferon-Independent Anti-HSV-1 Responses Through Viral and Host Targets

Quick responses to viral infections, which are essential for controlling viral diseases, are typically mediated by interferons. Herpes simplex virus 1 (HSV-1) switches between lytic and latent infections in neurons. Here we show that host early growth response (Egr) genes (including Egr1-Egr4), which are not interferon-stimulated genes, are generally upregulated in HSV-1-infected neuronal cells and acutely infected mouse ganglia. Surprisingly, Egr1 upregulation is independent of previously reported pathways upstream of Egr1 expression but dependent on viral protein ICP0. EGR1, in turn, represses HSV-1 replication in neuronal cells. Recombinant HSV-1 expressing EGR1 exhibits reduced replication in mouse ganglia and brainstems in vivo. Mechanistically, EGR1 binds to sites within the viral latency-associated transcript (LAT) gene promoter to increase LAT expression, which is known to favor repression of viral lytic genes. Concurrently, EGR1 can stimulate the expression of host immune proteins IRF7 and ISG15, and IRF7 is required for the anti-HSV-1 function of EGR1. Interestingly, both EGR1 and IRF7 suppress HSV-1 replication independent of interferons. Furthermore, EGR2, EGR3, and EGR4 can enhance LAT and IRF7 expression too. In summary, EGR proteins are upregulated during HSV-1 infection and mediate interferon-independent antiviral responses through both viral and host targets.