Alpha-herpesviruses are neurotropic pathogens that include the human viruses varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2, and the animal virus pseudorabies virus (PRV). These viruses spread into the nervous system by directed axonal transport to sensory neuron cell bodies in peripheral ganglia, where life-long latent infections are established. Infections are typically not life threatening in healthy individuals, however, these viruses have the capacity to spread trans-synaptically to enter the brain by circuit-specific routes. Once in the brain, the resulting encephalitis is lethal in the majority of cases. The long-term goals of my studies are to determine the mechanisms by which alpha-herpesviruses spread in the nervous system, and to identify the factors governing disease outcome. This application will focus on virus spread in the axons of sensory neurons. Specifically: Using infectious clone mutagenesis methods, viruses will be isolated carrying mutations in the genes encoding each tegument protein. The mutant viruses will be screened for defects in capsid transport in axons by time-lapse tracking of capsids fused to the green-fluorescence protein. Structure/function analysis of tegument proteins required for capsid transport will be initiated. In this way, the role of the viral tegument proteins in capsid transport will be definitively tested. These proteins are expected to both tether capsids to microtubule motors and regulate motor activity, as no other class of viral proteins are known to associate with capsids and be exposed to the host cytosol simultaneously. The results of these studies will determine how alpha-herpesviruses move directionally within sensory neurons. This will serve as a first step to identifying the molecular mechanisms of viral transport, and to addressing the larger question of virus spread in the vertebrate nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI056346-01A1
Application #
6779353
Study Section
Virology Study Section (VR)
Program Officer
Beisel, Christopher E
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$297,000
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Koenigsberg, Andrea L; Heldwein, Ekaterina E (2018) The dynamic nature of the conserved tegument protein UL37 of herpesviruses. J Biol Chem 293:15827-15839
Koenigsberg, Andrea L; Heldwein, Ekaterina E (2017) Crystal Structure of the N-Terminal Half of the Traffic Controller UL37 from Herpes Simplex Virus 1. J Virol 91:
Richards, Alexsia L; Sollars, Patricia J; Pitts, Jared D et al. (2017) The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion. PLoS Pathog 13:e1006741
Huffman, Jamie B; Daniel, Gina R; Falck-Pedersen, Erik et al. (2017) The C Terminus of the Herpes Simplex Virus UL25 Protein Is Required for Release of Viral Genomes from Capsids Bound to Nuclear Pores. J Virol 91:
Liu, Yun-Tao; Jiang, Jiansen; Bohannon, Kevin Patrick et al. (2017) A pUL25 dimer interfaces the pseudorabies virus capsid and tegument. J Gen Virol 98:2837-2849
Pomeranz, Lisa E; Ekstrand, Mats I; Latcha, Kaamashri N et al. (2017) Gene Expression Profiling with Cre-Conditional Pseudorabies Virus Reveals a Subset of Midbrain Neurons That Participate in Reward Circuitry. J Neurosci 37:4128-4144
Smith, Gregory A (2017) Assembly and Egress of an Alphaherpesvirus Clockwork. Adv Anat Embryol Cell Biol 223:171-193
Daniel, Gina R; Sollars, Patricia J; Pickard, Gary E et al. (2016) The pseudorabies virus protein, pUL56, enhances virus dissemination and virulence but is dispensable for axonal transport. Virology 488:179-86

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