EGR1 Upregulation During Encephalitic Viral Infections Contributes to Inflammation and Cell Death



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Early growth response 1 (EGR1) is an immediate early gene and transcription factor previously found to be significantly upregulated in human astrocytoma cells infected with Venezuelan equine encephalitis virus (VEEV). Loss of EGR1 resulted in decreased cell death, but had no significant impact on viral replication. Here, we extend these studies to determine the impacts of EGR1 on gene expression following viral infection in vitro and on animal survival and viral dissemination in vivo. Inflammatory genes CXCL3, CXCL8, and CXCL10 were found to be upregulated in VEEV infected cells in an EGR1 dependent manner. Additionally, other transcription factors, including EGR1 itself, as well as ATF3, FOS, JUN, EGR2, and EGR4 were found to be transcriptionally dependent on EGR1. We also examined EGR1’s transcriptional influence on gene expression in response to infection with other alphaviruses including eastern equine encephalitis virus (EEEV), Sindbis virus (SINV), and chikungunya virus (CHIKV), as well as Zika virus (ZIKV) and Rift Valley fever virus (RVFV), members of Flaviviridae and Phenuiviridae families, respectively. EGR1 was significantly upregulated to varying degrees in EEEV, CHIKV, RVFV, SINV and ZIKV, infected astrocytoma cells. Genes that were identified as being differentially upregulated following infection and also transcriptionally dependent on EGR1 included ATF3 (EEEV, CHIKV), JUN (EEEV), KLF4 (ZIKV, RVFV), CXCL3 (EEEV), CXCL8 (EEEV), CXCL10 (EEEV, RVFV), TNF-α (EEEV, ZIKV), and PTGS2 (EEEV). Additionally, inhibition of the inflammatory gene PTGS2 with Celecoxib, a small molecule inhibitor, rescued astrocytoma cells from VEEV induced cell death but had no impact on viral titers. Loss of EGR1 did not protect against VEEV induced mortality in vivo but EGR1-/- mice had delayed onset of clinical symptoms as well as delayed viral replication within the brain as compared to wild-type mice. Collectively, these results suggest that EGR1 induction following viral infection stimulates multiple inflammatory mediators. Managing inflammation and cell death in response to viral infection is of utmost importance, especially during VEEV infection where survivors are at-risk for neurological sequalae.



Alphaviruses, Astrocytes, EGR1, Inflammation, Venezuelan equine encephalitis