Egr-1 is involved in the gene expression and the replication of several viruses such as Epstein Barr virus [31, 32], HSV-1 [17, 33, 34], JC virus , orthopox virus , murine corona virus , rabies virus [38, 39], borna disease virus , human foamy virus , Japanese encephalitis virus , HTLV-I [41, 42] and HTLV-II . In most cases, Egr-1 was induced after the virus targeted neural cells and lymphocytes. Our results have demonstrated an induction of Egr-1 protein upon HSV-1 infection in epithelial cells such as VERO and SIRC (a corneal cell line). This observation suggests that Egr-1 could play a role in host cellular responses to HSV-1 lytic infection.
Several pathways are known to regulate the induction of Egr-1 including p38/MAPK , JNK , MEK/ERK , CREB pathway , and NFкB activation [27, 28]. By inhibiting the pathways known to be involved in Egr1 induction, we determined that NFкB and CREB play roles in Egr1 expression induced by HSV-1. CREB is activated and stabilized by HSV-1 ICP10 and can modulate viral-induced apoptosis . Studies have reported the presence of NFкB regulatory sequence  and CRE  in the human Egr-1 promoter. Transient activation of NFкB during the first few minutes of HSV-1 infection has been reported [48, 49]. In addition, most of the up-regulated mRNA upon infection was NFкB-dependent . Furthermore, NFкB-dependent gene expression is directly related to a number of stress-induced activities in eukaryotic cells . Since Egr-1 is induced by stress and is known to control a variety of divergent cellular responses, it is possible that this induction is NFкB-dependent. Therefore from the host cell standpoint, viral infection can be considered as a stress and Egr1 is rapidly induced to turn on various cellular responses.
Our previous study showed that Egr1 can bind to the Egr1 binding element (EBE) located in the intron of ICP22 and thus regulate the activity of both ICP22 and ICP4 . Since Egr1 is expressed in neural tissues, it could play a role in the maintenance of latency and subsequent reactivation. In addition, our preliminary studies revealed that Egr1 induced by viral infection was sufficient to interact with the ICP22 EBE during the lytic infection of SIRC and the over-expression of Egr-1 enhanced HSV-1 gene expression, replication, and release of infectious viruses (unpublished data). Together, these results suggest the involvement of Egr-1 in HSV-1 gene expression/replication via regulation of α-genes. Recombinant virus over-expressing Egr-1 and stable cell lines containing siRNA repressing Egr-1 are being constructed to further investigate the roles of Egr-1 during HSV-1 lytic infections.
It is not known which viral proteins are required for Egr-1 induction. It is likely that the binding of the viruses to the cell surface is sufficient to trigger the expression of Egr-1. Viral binding to the target cell is mediated by envelope glycoprotein gB, gC, or gD and the entry is mediated by gD to one of the cell surface receptors, such as the Herpes Virus Entry Mediator (HVEM)), heparan sulfate, nectin-1/2, and cell adhesion molecules from the immunoglobulin superfamily . HVEM belongs to the superfamily of TNF (tumor necrosis factor)/NGF (nerve growth factor) receptors , and has been identified independently as TR2 (TNF receptor like-2) . The Egr-1 gene can be regulated by TNF  and NGF  in cultured cells, and NFкB can be activated by the gD/HVEM . Therefore, Egr-1 induction quite possibly can be correlated to the binding of viral glycoprotein to HVEM or other cellular surface receptors. Additional experiments are required to determine the induction mechanisms of Egr-1 by viral infection.