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The Role of IKKβ in Venezuelan Equine Encephalitis Virus Infection

Journal Article · · PLoS ONE
 [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [2];  [2]
  1. George Mason Univ., Manassas, VA (United States); George Mason Univ., Fairfax, VA
  2. George Mason Univ., Manassas, VA (United States)
  3. Serpin Pharma LLC, Manassas, VA (United States)
+ Show Author Affiliations
Venezuelan equine encephalitis virus (VEEV) belongs to the genus Alphavirus, family Togaviridae. VEEV infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the NF-kB cascade in the in vivo pathology. Initial studies indicated that at early time points of VEEV infection, the NF-kB complex was activated in cells infected with the TC-83 strain of VEEV. One upstream kinase that contributes to the phosphorylation of p65 is the IKKb component of the IKK complex. Our previous studies with Rift valley fever virus, which exhibited early activation of the NF-kB cascade in infected cells, had indicated that the IKKb component underwent macromolecular reorganization to form a novel low molecular weight form unique to infected cells. This prompted us to investigate if the IKK complex undergoes a comparable macromolecular reorganization in VEEV infection. Size-fractionated VEEV infected cell extracts indicated a macromolecular reorganization of IKKb in VEEV infected cells that resulted in formation of lower molecular weight complexes. Well-documented inhibitors of IKKb function, BAY-11-7082, BAY-11-7085 and IKK2 compound IV, were employed to determine whether IKKb function was required for the production of infectious progeny virus. A decrease in infectious viral particles and viral RNA copies was observed with inhibitor treatment in the attenuated and virulent strains of VEEV infection. In order to further validate the requirement of IKKb for VEEV replication, we overexpressed IKKb in cells and observed an increase in viral titers. In contrast, studies carried out using IKKb-/- cells demonstrated a decrease in VEEV replication. In vivo studies demonstrated that inhibitor treatment of TC-83 infected mice increased their survival. Finally, proteomics studies have revealed that IKKb may interact with the viral protein nsP3. In conclusion, our studies have revealed that the host IKKb protein may be critically involved in VEEV replication.
Research Organization:
George Mason Univ., Fairfax, VA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
SC0001599
OSTI ID:
1904551
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 2 Vol. 9; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (8)

Genetic control of alphavirus pathogenesis journal August 2018
Venezuelan equine encephalitis virus non-structural protein 3 (nsP3) interacts with RNA helicases DDX1 and DDX3 in infected cells journal July 2016
The role of the IKK complex in viral infections journal August 2014
Efficacy of Host-Kinase Inhibitors as Antiviral Agents Against Venezuelan Equine Encephalitis Virus other January 2018
Interactions of Alphavirus nsP3 Protein with Host Proteins journal January 2018
The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last journal February 2018
Current Understanding of the Molecular Basis of Venezuelan Equine Encephalitis Virus Pathogenesis and Vaccine Development journal February 2019
Phosphorylation of Single Stranded RNA Virus Proteins and Potential for Novel Therapeutic Strategies journal October 2015

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
alphaviruses
biotechnology
cell viability testing
phosphorylation
transcription factors
transfection
viral diseases
viral replication