Spread of neuroinvasive herpesviruses from sensory neurons to the eye, brain or from mother to newborn are leading causes of morbidity and mortality associated with infections by this class of pathogens. Herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) are representative members of the two genuses of neuroinvasive herpesviruses (simplexviruses &varicelloviruses), both belonging to the alpha-herpesvirus subfamily. Both viruses establish life-long latent infections in sensory neurons of the peripheral nervous system, and both are established models for use in the laboratory. In this proposal, we leverage our strengths in infectious clone mutagenesis and live-cell viral tracking methods to address the mechanisms of HSV-1 and PRV spread within sensory neurons. Viral transport to the site of latency and transport following reactivation to peripheral innervated tissues are both critical to the viral infectious cycle, and both of these stages of infection are modeled using cultured sensory neurons and examined in animals to investigate the mechanisms of virus intracellular trafficking. In addition, new evidence is provided indicating that the very large herpesvirus tegument protein, VP1/2, is responsible for intracellular transport of capsids, and new tools for dissecting the mechanism of viral transport along microtubules are employed.

Public Health Relevance

Neuroinvasive alpha-herpesviruses are the causative agents of a number of severe diseases including shingles, encephalitis, neonatal infections and herpes keratitis (the leading cause of infectious blindness in the USA and other industrialized nations). This proposal focuses on understanding the cellular mechanisms used by herpesviruses to spread within the nervous system and cause disease, with the long term goal of developing new treatments to intervene with disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI056346-06A2
Application #
7786915
Study Section
Virology - A Study Section (VIRA)
Program Officer
Challberg, Mark D
Project Start
2003-07-01
Project End
2014-11-30
Budget Start
2009-12-15
Budget End
2010-11-30
Support Year
6
Fiscal Year
2010
Total Cost
$186,813
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
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:
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
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
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:
Smith, Gregory A (2017) Assembly and Egress of an Alphaherpesvirus Clockwork. Adv Anat Embryol Cell Biol 223:171-193
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
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
Richards, Alexsia L; Sollars, Patricia J; Smith, Gregory A (2016) New tools to convert bacterial artificial chromosomes to a self-excising design and their application to a herpes simplex virus type 1 infectious clone. BMC Biotechnol 16:64
Maier, Oana; Sollars, Patricia J; Pickard, Gary E et al. (2016) Visualizing Herpesvirus Procapsids in Living Cells. J Virol 90:10182-10192
Huffmaster, Nicholas J; Sollars, Patricia J; Richards, Alexsia L et al. (2015) Dynamic ubiquitination drives herpesvirus neuroinvasion. Proc Natl Acad Sci U S A 112:12818-23

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