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Home / Equine Research Bank / Front Microbiol / Venezuelan Equine Encephalitis Virus Capsid Implicated in In...
Frontiers in microbiology2018; 9; 3126; doi: 10.3389/fmicb.2018.03126

Venezuelan Equine Encephalitis Virus Capsid Implicated in Infection-Induced Cell Cycle Delay in vitro.

Abstract: Venezuelan equine encephalitis virus (VEEV) is a positive sense, single-stranded RNA virus and member of the New World alphaviruses. It causes a biphasic febrile illness that can be accompanied by central nervous system involvement and moderate morbidity in humans and severe mortality in equines. The virus has a history of weaponization, lacks FDA-approved therapeutics and vaccines in humans, and is considered a select agent. Like other RNA viruses, VEEV replicates in the cytoplasm of infected cells and eventually induces apoptosis. The capsid protein, which contains a nuclear localization and a nuclear export sequence, induces a shutdown of host transcription and nucleocytoplasmic trafficking. Here we show that infection with VEEV causes a dysregulation of cell cycling and a delay in the G/G phase in Vero cells and U87MG astrocytes. Cells infected with VEEV encoding a capsid NLS mutant or treated with the capsid-importin α interaction inhibitor G281-1485 were partially rescued from this cell cycle dysregulation. Pathway analysis of previously published RNA-sequencing data from VEEV infected U87MG astrocytes identified alterations of canonical pathways involving cell cycle, checkpoint regulation, and proliferation. Multiple cyclins including cyclin D1, cyclin A2 and cyclin E2 and other regulators of the cell cycle were downregulated in infected cells in a capsid NLS dependent manner. Loss of Rb phosphorylation, which is a substrate for cyclin/cdk complexes was also observed. These data demonstrate the importance of capsid nuclear localization and/or importin α binding for inducing cell cycle arrest and transcriptional downregulation of key cell cycle regulators.
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Publication Date: 2018-12-18 PubMed ID: 30631316PubMed Central: PMC6315117DOI: 10.3389/fmicb.2018.03126Google 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 study investigates how Venezuelan equine encephalitis virus (VEEV) causes disruption in cell growth cycles and implicates its capsid protein in the process which might open new therapeutic directions.

Understanding Venezuelan Equine Encephalitis Virus (VEEV)

  • The VEEV is an RNA virus capable of causing a feverish illness that exhibits two distinct stages or phases. It has the potential to cause medium-level mortality in humans and much higher fatality rates in horses. The virus has been weaponized in the past, with no FDA-approved treatment or vaccine for humans, and is categorized as a “select agent,” indicating its potential for use in biological warfare.
  • The virus works by replicating itself in the cytoplasm of infected cells and consequently causes those cells to undergo apoptosis or cell death.
  • The VEEV features a capsid protein, containing particulars for nuclear localization and export, which induces a shutdown in host transcription and nuclear-cytoplasmic trafficking procedures.

VEEV’s Impact on Cell Cycle & G/G Phase Delay

  • This research demonstrates that VEEV infection leads to a significant dysregulation in cell cycling and a delay in the G/G phase, affecting both Vero cells and U87MG astrocytes. This essentially inhibits the regular growth and replication of these cells, aiding in the spread and severity of the infection.
  • Virus-induced dysregulation in the cell cycle could be partially mitigated when cells were either infected with a version of VEEV that encodes a nuclear localization sequence (NLS) mutant in its capsid protein or when treated with a specific interaction inhibitor.

Effects on Cell Cycle Regulation Pathways

  • Analysis of gene expression data from infected U87MG astrocytes revealed alterations in key cellular mechanisms impacting cell cycle regulation and proliferation.
  • VEEV infection resulted in the down-regulation of multiple cyclins, including cyclin D1, cyclin A2, and cyclin E2, along with other important regulators of the cell cycle. This suppression of key cell cycle components was dependent on the nuclear localization sequence (NLS) of the VEEV capsid.
  • A significant loss of Rb (Retinoblastoma protein) phosphorylation was observed, which is a known substrate for cyclin/cdk complexes, indicating the downregulation of essential cell cycle interventions.

Conclusion

  • The findings underscore the importance of VEEV capsid’s nuclear localization and/or importin α binding in inducing cell cycle disruption and transcriptional downregulation of important cell cycle regulators. Ultimately, understanding these mechanisms could assist in developing new targeted treatment strategies for VEEV and related viruses.

Cite This Article

APA
Lundberg L, Fontenot J, Lin SC, Pinkham C, Carey BD, Campbell CE, Kehn-Hall K. (2018). Venezuelan Equine Encephalitis Virus Capsid Implicated in Infection-Induced Cell Cycle Delay in vitro. Front Microbiol, 9, 3126. https://doi.org/10.3389/fmicb.2018.03126

Publication

Frontiers in microbiology
ISSN: 1664-302X
NlmUniqueID: 101548977
Country: Switzerland
Language: English
Volume: 9
Pages: 3126
PII: 3126

Researcher Affiliations

Lundberg, Lindsay
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, United States.
Fontenot, Jacque
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, United States.
Lin, Shih-Chao
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, United States.
Pinkham, Chelsea
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, United States.
Carey, Brian D
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, United States.
Campbell, Catherine E
  • DCE Consulting, Vienna, VA, United States.
Kehn-Hall, Kylene
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, United States.

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This article has been cited 7 times.
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