This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, M.
Right arrow Articles by Enquist, L. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, M.
Right arrow Articles by Enquist, L. W.

 Previous Article  |  Next Article 

Journal of Virology, May 1999, p. 4350-4359, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Retrograde, Transneuronal Spread of Pseudorabies Virus in Defined Neuronal Circuitry of the Rat Brain Is Facilitated by gE Mutations That Reduce Virulence

M. Yang,1 J. P. Card,2 R. S. Tirabassi,3 R. R. Miselis,1 and L. W. Enquist3,*

Department of Animal Biology, University of Pennsylvania Veterinary School, Philadelphia, Pennsylvania 191041; Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 152602; and Department of Molecular Biology, Princeton University, Princeton, New Jersey 085443

Received 9 November 1998/Accepted 11 February 1999

The pseudorabies virus (PRV) gE gene encodes a multifunctional membrane protein found in infected cell membranes and in the virion envelope. Deletion of the gE gene results in marked attenuation of the virus in almost every animal species tested that is permissive for PRV. A common inference is that gE mutants are less virulent because they have reduced ability to spread from cell to cell; e.g., gE mutants infect fewer cells and, accordingly, animals live longer. In this report, we demonstrate that this inference does not hold in a rat experimental model for virus invasion of the brain. We find that animals infected with gE mutants live longer despite extensive retrograde, transneuronal spread of virus in the rat brain. In this model of brain infection, virus is injected into the stomach musculature and virions spread to the brain in long axons of brain stem neurons that give rise to the tenth cranial nerve (the vagus). The infection then spreads from neuron to neuron in well-defined, and physically separated, areas of the brain involved in autonomic regulation of the viscera. We examined the progression of infection of five PRV strains in this circuitry: the wild-type PRV-Becker strain, the attenuated PRV-Bartha vaccine strain, and three gE mutants isogenic with the PRV-Becker strain. By 60 to 67 h after infection, all PRV-Becker-infected animals were dead. Analysis of Becker-infected rats killed prior to virus-induced death demonstrated that the virus had established an infection only in the primary vagal neurons connected directly to the stomach and synaptically linked neurons in the immediate vicinity of the caudal brain stem. There was little spread to other neurons in the vagus circuitry. In contrast, rats infected with PRV-Bartha or PRV-Becker gE mutants survived to at least 96 h and exhibited few overt signs of disease. Despite this long survival and the lack of symptoms, brains of animals sacrificed at this time revealed extensive transsynaptic infection not only of the brain stem but also of areas of the forebrain synaptically linked to neurons in the brain stem. This finding provides evidence that the gE protein plays a role in promoting symptoms of infection and death in animals that is independent of neuron-to-neuron spread during brain infection. When this early virulence function is not active, animals live longer, resulting in more extensive spread of virus in the brain.

* Corresponding author. Mailing address: 314 Schultz Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ 08544. Phone: (609) 258-2415. Fax: (609) 258-1035. E-mail: Lenquist{at}molbio.princeton.edu.

Journal of Virology, May 1999, p. 4350-4359, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Curanovic, D., Lyman, M. G., Bou-Abboud, C., Card, J. P., Enquist, L. W. (2009). Repair of the UL21 Locus in Pseudorabies Virus Bartha Enhances the Kinetics of Retrograde, Transneuronal Infection In Vitro and In Vivo. J. Virol. 83: 1173-1183 [Abstract] [Full Text]  
  • Olsen, L. M., Ch'ng, T. H., Card, J. P., Enquist, L. W. (2006). Role of Pseudorabies Virus Us3 Protein Kinase during Neuronal Infection.. J. Virol. 80: 6387-6398 [Abstract] [Full Text]  
  • Paulus, C., Sollars, P. J., Pickard, G. E., Enquist, L. W. (2006). Transcriptome Signature of Virulent and Attenuated Pseudorabies Virus-Infected Rodent Brain. J. Virol. 80: 1773-1786 [Abstract] [Full Text]  
  • Pomeranz, L. E., Reynolds, A. E., Hengartner, C. J. (2005). Molecular Biology of Pseudorabies Virus: Impact on Neurovirology and Veterinary Medicine. Microbiol. Mol. Biol. Rev. 69: 462-500 [Abstract] [Full Text]  
  • Ch'ng, T. H., Enquist, L.W. (2005). Neuron-to-Cell Spread of Pseudorabies Virus in a Compartmented Neuronal Culture System. J. Virol. 79: 10875-10889 [Abstract] [Full Text]  
  • Brittle, E. E., Reynolds, A. E., Enquist, L. W. (2004). Two Modes of Pseudorabies Virus Neuroinvasion and Lethality in Mice. J. Virol. 78: 12951-12963 [Abstract] [Full Text]  
  • Rinaman, L., Schwartz, G. (2004). Anterograde Transneuronal Viral Tracing of Central Viscerosensory Pathways in Rats. J. Neurosci. 24: 2782-2786 [Abstract] [Full Text]  
  • Klopfleisch, R., Teifke, J. P., Fuchs, W., Kopp, M., Klupp, B. G., Mettenleiter, T. C. (2004). Influence of Tegument Proteins of Pseudorabies Virus on Neuroinvasion and Transneuronal Spread in the Nervous System of Adult Mice after Intranasal Inoculation. J. Virol. 78: 2956-2966 [Abstract] [Full Text]  
  • Flamand, A., Bennardo, T., Babic, N., Klupp, B. G., Mettenleiter, T. C. (2001). The Absence of Glycoprotein gL, but Not gC or gK, Severely Impairs Pseudorabies Virus Neuroinvasiveness. J. Virol. 75: 11137-11145 [Abstract] [Full Text]  
  • DeFalco, J., Tomishima, M., Liu, H., Zhao, C., Cai, X., Marth, J. D., Enquist, L., Friedman, J. M. (2001). Virus-Assisted Mapping of Neural Inputs to a Feeding Center in the Hypothalamus. Science 291: 2608-2613 [Abstract] [Full Text]  
  • Tirabassi, R. S., Enquist, L. W. (2000). Role of the Pseudorabies Virus gI Cytoplasmic Domain in Neuroinvasion, Virulence, and Posttranslational N-Linked Glycosylation. J. Virol. 74: 3505-3516 [Abstract] [Full Text]  
  • Rinaman, L., Levitt, P., Card, J. P. (2000). Progressive Postnatal Assembly of Limbic-Autonomic Circuits Revealed by Central Transneuronal Transport of Pseudorabies Virus. J. Neurosci. 20: 2731-2741 [Abstract] [Full Text]  
  • Kim, J.-S., Enquist, L. W., Card, J. P. (1999). Circuit-Specific Coinfection of Neurons in the Rat Central Nervous System with Two Pseudorabies Virus Recombinants. J. Virol. 73: 9521-9531 [Abstract] [Full Text]  
  • Tomishima, M.J., Enquist, L.W. (2001). A conserved {alpha}-herpesvirus protein necessary for axonal localization of viral membrane proteins. JCB 154: 741-752 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»