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Journal of virology2016; 90(7); 3558-3572; doi: 10.1128/JVI.02827-15

Venezuelan Equine Encephalitis Virus Induces Apoptosis through the Unfolded Protein Response Activation of EGR1.

Abstract: Venezuelan equine encephalitis virus (VEEV) is a previously weaponized arthropod-borne virus responsible for causing acute and fatal encephalitis in animal and human hosts. The increased circulation and spread in the Americas of VEEV and other encephalitic arboviruses, such as eastern equine encephalitis virus and West Nile virus, underscore the need for research aimed at characterizing the pathogenesis of viral encephalomyelitis for the development of novel medical countermeasures. The host-pathogen dynamics of VEEV Trinidad donkey-infected human astrocytoma U87MG cells were determined by carrying out RNA sequencing (RNA-Seq) of poly(A) and mRNAs. To identify the critical alterations that take place in the host transcriptome following VEEV infection, samples were collected at 4, 8, and 16 h postinfection and RNA-Seq data were acquired using an Ion Torrent PGM platform. Differential expression of interferon response, stress response factors, and components of the unfolded protein response (UPR) was observed. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the UPR was activated, as the expression of both activating transcription factor 4 (ATF4) and CHOP (DDIT3), critical regulators of the pathway, was altered after infection. Expression of the transcription factor early growth response 1 (EGR1) was induced in a PERK-dependent manner. EGR1(-/-) mouse embryonic fibroblasts (MEFs) demonstrated lower susceptibility to VEEV-induced cell death than isogenic wild-type MEFs, indicating that EGR1 modulates proapoptotic pathways following VEEV infection. The influence of EGR1 is of great importance, as neuronal damage can lead to long-term sequelae in individuals who have survived VEEV infection. Objective: Alphaviruses represent a group of clinically relevant viruses transmitted by mosquitoes to humans. In severe cases, viral spread targets neuronal tissue, resulting in significant and life-threatening inflammation dependent on a combination of virus-host interactions. Currently there are no therapeutics for infections cause by encephalitic alphaviruses due to an incomplete understanding of their molecular pathogenesis. Venezuelan equine encephalitis virus (VEEV) is an alphavirus that is prevalent in the Americas and that is capable of infecting horses and humans. Here we utilized next-generation RNA sequencing to identify differential alterations in VEEV-infected astrocytes. Our results indicated that the abundance of transcripts associated with the interferon and the unfolded protein response pathways was altered following infection and demonstrated that early growth response 1 (EGR1) contributed to VEEV-induced cell death.
Copyright © 2016 Baer et al.
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Publication Date: 2016-01-20 PubMed ID: 26792742PubMed Central: PMC4794670DOI: 10.1128/JVI.02827-15Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates how Venezuelan equine encephalitis virus (VEEV) interact with human cells, triggering a cellular stress response that may lead to apoptosis, or programmed cell death. By understanding this interaction and the role of the protein EGR1 in this process, new potential treatments for viral encephalitis could be developed.

Understanding Venezuelan Equine Encephalitis Virus (VEEV)

  • VEEV is an arthropod-borne virus that has previously been deployed as a biological weapon. It is responsible for acute and potentially fatal encephalitis in animals and humans.
  • The virus is increasingly prevalent in the Americas, and so understanding its pathogenesis – the development of the disease – is crucial for the development of medical interventions.
  • This research specifically uses VEEV Trinidad donkey-infected human astrocytoma U87MG cells to study host-pathogen dynamics. This allows the researchers to examine how the virus interacts with human cell structures and proteins.

Studying VEEV-Host Interaction

  • The researchers used RNA sequencing to study changes in the host transcriptome – the complete set of RNA transcripts, both coding and non-coding, produced by the genome – after VEEV infection at different post-infection intervals: 4, 8, and 16 hours.
  • The data suggested an altered expression of the interferon response, stress response factors, and components of the unfolded protein response (UPR).
  • Specifically, an activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the UPR was observed.

Role of EGR1 in VEEV-Induced Cell Death

  • The data collected shows an altered expression of activating transcription factor 4 (ATF4) and CHOP (DDIT3), which are critical regulators in the UPR pathway.
  • The expression of the transcription factor early growth response 1 (EGR1) was found to be induced in a PERK-dependent manner. This is significant as it indicates EGR1 may play an essential role in the cell death caused by VEEV.
  • This hypothesis was further supported by experiments using mouse embryonic fibroblasts (MEFs) with and without the gene for EGR1. The MEFs without EGR1 showed less susceptibility to cell death following VEEV infection, suggesting that EGR1 modulates proapoptotic pathways.
  • The role of EGR1 in VEEV-triggered cell death could be significant in developing treatments for viral encephalitis, since neuronal damage and the associated long-term effects are serious complications for those who survive VEEV infections.

Cite This Article

APA
Baer A, Lundberg L, Swales D, Waybright N, Pinkham C, Dinman JD, Jacobs JL, Kehn-Hall K. (2016). Venezuelan Equine Encephalitis Virus Induces Apoptosis through the Unfolded Protein Response Activation of EGR1. J Virol, 90(7), 3558-3572. https://doi.org/10.1128/JVI.02827-15

Publication

Journal of virology
ISSN: 1098-5514
NlmUniqueID: 0113724
Country: United States
Language: English
Volume: 90
Issue: 7
Pages: 3558-3572

Researcher Affiliations

Baer, Alan
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, Virginia, USA.
Lundberg, Lindsay
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, Virginia, USA.
Swales, Danielle
  • MRIGlobal, Global Health Security, Rockville, Maryland, USA.
Waybright, Nicole
  • MRIGlobal, Global Health Security, Rockville, Maryland, USA.
Pinkham, Chelsea
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, Virginia, USA.
Dinman, Jonathan D
  • University of Maryland, Department of Cell Biology and Molecular Genetics, College Park, Maryland, USA.
Jacobs, Jonathan L
  • MRIGlobal, Global Health Security, Rockville, Maryland, USA jjacobs@mriglobal.org kkehnhal@gmu.edu.
Kehn-Hall, Kylene
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, Virginia, USA jjacobs@mriglobal.org kkehnhal@gmu.edu.

MeSH Terms

  • Animals
  • Apoptosis
  • Cell Line
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Encephalitis Virus, Venezuelan Equine / physiology
  • Gene Expression Profiling
  • Host-Pathogen Interactions
  • Humans
  • Mice
  • Mice, Knockout
  • Unfolded Protein Response

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Citations

This article has been cited 39 times.
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