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Journal of Virology, December 2009, p. 12432-12442, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.00564-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Acute Infection with Venezuelan Equine Encephalitis Virus Replicon Particles Catalyzes a Systemic Antiviral State and Protects from Lethal Virus Challenge{triangledown}

Jennifer L. Konopka,1,2* Joseph M. Thompson,1,2,{dagger} Alan C. Whitmore,2 Drue L. Webb,1,2 and Robert E. Johnston1,2

Department of Microbiology and Immunology,1 Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275992

Received 19 March 2009/ Accepted 17 September 2009

The host innate immune response provides a critical first line of defense against invading pathogens, inducing an antiviral state to impede the spread of infection. While numerous studies have documented antiviral responses within actively infected tissues, few have described the earliest innate response induced systemically by infection. Here, utilizing Venezuelan equine encephalitis virus (VEE) replicon particles (VRP) to limit infection to the initially infected cells in vivo, a rapid activation of the antiviral response was demonstrated not only within the murine draining lymph node, where replication was confined, but also within distal tissues. In the liver and brain, expression of interferon-stimulated genes was detected by 1 to 3 h following VRP footpad inoculation, reaching peak expression of >100-fold over that in mock-infected animals. Moreover, mice receiving a VRP footpad inoculation 6, 12, or 24 h prior to an otherwise lethal VEE footpad challenge were completely protected from death, including a drastic reduction in challenge virus titers. VRP pretreatment also provided protection from intranasal VEE challenge and extended the average survival time following intracranial challenge. Signaling through the interferon receptor was necessary for antiviral gene induction and protection from VEE challenge. However, VRP pretreatment failed to protect mice from a heterologous, lethal challenge with vesicular stomatitis virus, yet conferred protection following challenge with influenza virus. Collectively, these results document a rapid modulation of the host innate response within hours of infection, capable of rapidly alerting the entire animal to pathogen invasion and leading to protection from viral disease.

* Corresponding author. Present address: Department of Pediatrics, Division of Infectious Diseases, Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 343-8911. Fax: (615) 343-9723. E-mail: jkonops{at}gmail.com

{triangledown} Published ahead of print on 30 September 2009.

{dagger} Present address: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519.

Journal of Virology, December 2009, p. 12432-12442, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.00564-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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