Venezuelan equine encephalitis virus E1 protein interacts with PDIA6 and PDI inhibition reduces alphavirus production

Lauren Panny; Ivan Akrhymuk; Nicole Bracci; Caitlin Woodson; Rafaela Flor; Isaac Elliott; Weidong Zhou; Aarthi Narayanan; Catherine Campbell; Kylene Kehn-Hall

doi:10.1016/j.antiviral.2023.105560

Venezuelan equine encephalitis virus E1 protein interacts with PDIA6 and PDI inhibition reduces alphavirus production

Antiviral Res. 2023 Apr:212:105560. doi: 10.1016/j.antiviral.2023.105560. Epub 2023 Feb 22.

Authors

Affiliations

¹ Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA; Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA.
² Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA.
³ Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason University, Manassas, VA, 20110, USA.
⁴ Department of Biology, George Mason University, Fairfax, VA, 22030, USA.
⁵ DCE Consulting, Vienna, VA, 2218, USA.
⁶ Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA; Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA. Electronic address: kkehnhall@vt.edu.

PMID: 36822370
DOI: 10.1016/j.antiviral.2023.105560

Abstract

Venezuelan equine encephalitis virus (VEEV) is an alphavirus transmitted by mosquitos that can cause a febrile illness and induce severe neurological complications in humans and equine populations. Currently there are no FDA approved vaccines or antiviral treatments to combat VEEV. Proteomic techniques were utilized to create an interactome of the E1 fusion glycoprotein of VEEV. VEEV E1 interacted with a number of cellular chaperone proteins including protein disulfide isomerase family A member 6 (PDIA6). PDI inhibition through LOC14 and/or nitazoxanide treatment effectively decreased production of VEEV and other alphaviruses in vitro, including eastern equine encephalitis virus, Sindbis virus, and chikungunya virus. Decreased oxidoreductive capabilities of PDIs through LOC14 or nitazoxanide treatment impacted both early and late events in viral replication, including the production of non-infectious virions and decreased VEEV E1 disulfide bond formation. Results from this study identified PDIs as critical regulators of alphavirus replication and potential therapeutic targets.

Keywords: Alphavirus; E1; LOC14; Nitazoxanide; Protein disulfide isomerase; Venezuelan equine encephalitis virus.

Publication types

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

MeSH terms

Alphavirus*
Animals
Cell Line
Chikungunya virus*
Encephalitis Virus, Venezuelan Equine*
Encephalomyelitis, Venezuelan Equine* / drug therapy
Horses
Humans
Protein Disulfide-Isomerases / pharmacology
Protein Disulfide-Isomerases / therapeutic use
Proteomics
Virus Replication

Substances

nitazoxanide
PDIA6 protein, human
Protein Disulfide-Isomerases