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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Virology - A Study Section (VIRA)
Program Officer
Challberg, Mark D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Schools of Medicine
United States
Zip Code
Daniel, Gina R; Pegg, Caitlin E; Smith, Gregory A (2018) Dissecting the Herpesvirus Architecture by Targeted Proteolysis. J Virol 92:
Ruhge, Laura L; Huet, Alexis G E; Conway, James F et al. (2018) The Apical Region of the Herpes Simplex Virus Major Capsid Protein Promotes Capsid Maturation. J Virol 92:
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

Showing the most recent 10 out of 30 publications