EGR1 regulation of neuronal survival and inflammation following VEEV infection
Abstract
The molecular and cellular mechanisms of virulence for encephalitic alphaviruses, such as Venezuelan Equine Encephalitis virus (VEEV), remain a largely unknown and understudied area of infectious disease research. Importantly, a long-standing knowledge gap remains with regard to the host-pathogen interactions underpinning for their replication, which in turn has hampered efforts to successfully develop therapeutics and medical countermeasures aimed at combating these deadly viruses. Recent transcriptomic studies by our group demonstrated a significant and dramatic upregulation of early growth response 1 (EGR1) in VEEV-TrD infected human astrocytoma cells. EGR1 is a transcription factor associated with cellular stress response pathways, and our work has established a novel link between EGR1, the interferon response pathway and the unfolded protein response pathway – two pathways which are intimately associated with apoptosis. Loss of EGR1 resulted in lower susceptibility to VEEV induced cell death, indicating that EGR1 modulates pro-apoptotic pathways following infection. The influence of EGR1 on cell death is of great importance as neuronal damage can lead to longterm sequelae in individuals who have survived VEEV infection. Here we aim to extend our prior ch to determine which genes are transcriptionally dependent on EGR1 expression and whether they contribute to VEEV induced apoptosis. We will also study the importance of EGR1 on neuronal viability and inflammation in vivo through the use of EGR1 knockout mice. Finally, we will examine cellular and viral factors needed for EGR1 upregulation. This knowledge can be used to rationally develop EGR1 pathway inhibitors that can protect cells from VEEV induced cell death.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- HDTRA11810045
Entities
People
- Kylene Kehnhall
Organizations
- Defense Threat Reduction Agency
- George Mason University