The long term goal is to understand in molecular terms how a neurotropic herpes virus invades and spreads in the mammalian nervous system. Most alpha herpesviruses (e.g., herpes simplex virus HSV; varicella-zoster virus, VZV; and pseudorabies virus, PRV, display a striking neurotropism infecting both the peripheral and central nervous system, and do so in every animal species that can be infected. In PRV, two genes (gE, gI) are required for anterograde, but not retrograde spread in the nervous system of living animals. A new gene (Us9) was recently discovered that also is required for anterograde spread of PRV. All three gene products also influence virulence. Research in this proposal will continue a focused genetic and biochemical attack to determine the functions of the gE, gI and Us9 gene products in invasion, spread and pathogenesis in the nervous system.
Four specific aims are proposed to test a general model of directional spread of virus in the nervous system:
In aim 1, the localization and trafficking of gE, gI and Us9 proteins in cultured neurons and infected nervous system tissue will be determined.
In aim 2 alanine substitution mutations in the gE ectodomain will be analyzed to define sites of interaction with putative cellular receptors. In addition, the role of the gI cytoplasmic tail on gE function will be determined.
In aim 3, a genetic and biochemical analysis of Us9 will be initiated to determine its role in anterograde trans-neuronal spread. Finally, in aim 4: the role of gD, a viral ligand essential for virion infection, will be analyzed to determine if gD is involved in gE/gI/Us9-dependent and -independent spread of virus in defined neuronal circuits. The knowledge to be learned from completion of this work is important because the direction taken by the virus in a neuron after primary infection or reactivation from latency, as well the extent of spread in a neuronal circuit can be the difference between a minor peripheral infection or a lethal viral encephalitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033506-08
Application #
6490911
Study Section
Virology Study Section (VR)
Program Officer
Nunn, Michael
Project Start
1995-01-01
Project End
2004-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
8
Fiscal Year
2002
Total Cost
$373,825
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Hogue, Ian B; Card, J Patrick; Rinaman, Linda et al. (2018) Characterization of the neuroinvasive profile of a pseudorabies virus recombinant expressing the mTurquoise2 reporter in single and multiple injection experiments. J Neurosci Methods 308:228-239
Hogue, Ian B; Jean, Jolie; Esteves, Andrew D et al. (2018) Functional Carboxy-Terminal Fluorescent Protein Fusion to Pseudorabies Virus Small Capsid Protein VP26. J Virol 92:
Koyuncu, Orkide O; MacGibeny, Margaret A; Enquist, Lynn W (2018) Latent versus productive infection: the alpha herpesvirus switch. Future Virol 13:431-443
Harris, Greg M; Madigan, Nicolas N; Lancaster, Karen Z et al. (2017) Nerve Guidance by a Decellularized Fibroblast Extracellular Matrix. Matrix Biol 60-61:176-189
Enquist, Lynn W; Leib, David A (2017) Intrinsic and Innate Defenses of Neurons: Détente with the Herpesviruses. J Virol 91:
Bosse, Jens B; Enquist, Lynn W (2016) The diffusive way out: Herpesviruses remodel the host nucleus, enabling capsids to access the inner nuclear membrane. Nucleus 7:13-9
Song, Ren; Koyuncu, Orkide O; Greco, Todd M et al. (2016) Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion. MBio 7:e02145-15
Johnson, Blake N; Lancaster, Karen Z; Hogue, Ian B et al. (2016) 3D printed nervous system on a chip. Lab Chip 16:1393-400
Bosse, Jens B; Tanneti, Nikhila S; Hogue, Ian B et al. (2015) Open LED Illuminator: A Simple and Inexpensive LED Illuminator for Fast Multicolor Particle Tracking in Neurons. PLoS One 10:e0143547
Engel, Esteban A; Song, Ren; Koyuncu, Orkide O et al. (2015) Investigating the biology of alpha herpesviruses with MS-based proteomics. Proteomics 15:1943-56

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