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

Caitlin W Lehman; Amy Smith; Jamie Kelly; Jonathan L Jacobs; Jonathan D Dinman; Kylene Kehn-Hall

doi:10.3390/v14061210

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

Viruses. 2022 Jun 2;14(6):1210. doi: 10.3390/v14061210.

Authors

Caitlin W Lehman^{1

2}, Amy Smith^{1

2}, Jamie Kelly³, Jonathan L Jacobs⁴, Jonathan D Dinman³, Kylene Kehn-Hall^{1

2}

Affiliations

¹ Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
² Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
³ Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
⁴ American Type Culture Collection, Manassas, VA 20110, USA.

Abstract

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). The 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. Inflammatory genes CXCL3, CXCL8, CXCL10, TNF, and PTGS2 were upregulated in VEEV-infected cells, which was partially dependent on EGR1. Additionally, transcription factors, including EGR1 itself, as well as ATF3, FOS, JUN, KLF4, EGR2, and EGR4 were found to be partially transcriptionally dependent on EGR1. We also examined the role of EGR1 and the changes in 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 the 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 partially transcriptionally dependent on EGR1 in infected cells included ATF3 (EEEV, CHIKV, ZIKV), JUN (EEEV), KLF4 (SINV, ZIKV, RVFV), CXCL3 (EEEV, CHIKV, ZIKV), CXCL8 (EEEV, CHIKV, ZIKV, RVFV), CXCL10 (EEEV, RVFV), TNF-α (EEEV, ZIKV, RVFV), and PTGS2 (EEEV, CHIKV, ZIKV). 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. 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.

Keywords: EGR1; Venezuelan equine encephalitis; alphaviruses; astrocytes; inflammation.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Astrocytoma*
Cell Death
Cyclooxygenase 2 / genetics
Early Growth Response Protein 1
Encephalitis Virus, Venezuelan Equine* / genetics
Encephalomyelitis, Equine*
Humans
Inflammation
Sindbis Virus
Up-Regulation
Zika Virus Infection*
Zika Virus*

Substances

EGR1 protein, human
Early Growth Response Protein 1
Cyclooxygenase 2

Grants and funding

This work was funded through the Defense Threat Reduction Agency (DTRA), grant HDTRA1-21-1-0008 to KKH. Funders do not have any role in the design of the study and collection, analysis, and interpretation of data, nor in writing the manuscript.