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 #
5R01AI056346-09
Application #
8389634
Study Section
Virology - A Study Section (VIRA)
Program Officer
Challberg, Mark D
Project Start
2003-07-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
9
Fiscal Year
2013
Total Cost
$362,126
Indirect Cost
$109,927
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
Pitts, Jared D; Klabis, Jenifer; Richards, Alexsia L et al. (2014) Crystal structure of the herpesvirus inner tegument protein UL37 supports its essential role in control of viral trafficking. J Virol 88:5462-73
Zaichick, Sofia V; Bohannon, Kevin P; Hughes, Ami et al. (2013) The herpesvirus VP1/2 protein is an effector of dynein-mediated capsid transport and neuroinvasion. Cell Host Microbe 13:193-203
Zaichick, Sofia V; Bohannon, Kevin P; Smith, Gregory A (2011) Alphaherpesviruses and the cytoskeleton in neuronal infections. Viruses 3:941-81
Antinone, Sarah E; Zaichick, Sofia V; Smith, Gregory A (2010) Resolving the assembly state of herpes simplex virus during axon transport by live-cell imaging. J Virol 84:13019-30
Antinone, Sarah Elizabeth; Smith, Gregory Allan (2010) Retrograde axon transport of herpes simplex virus and pseudorabies virus: a live-cell comparative analysis. J Virol 84:1504-12
Van den Broeke, Celine; Deruelle, Matthias; Nauwynck, Hans J et al. (2009) The kinase activity of pseudorabies virus US3 is required for modulation of the actin cytoskeleton. Virology 385:155-60
Lee, Joy I; Sollars, Patricia J; Baver, Scott B et al. (2009) A herpesvirus encoded deubiquitinase is a novel neuroinvasive determinant. PLoS Pathog 5:e1000387
Coller, Kelly E; Smith, Gregory A (2008) Two viral kinases are required for sustained long distance axon transport of a neuroinvasive herpesvirus. Traffic 9:1458-70
Antinone, Sarah E; Shubeita, George T; Coller, Kelly E et al. (2006) The Herpesvirus capsid surface protein, VP26, and the majority of the tegument proteins are dispensable for capsid transport toward the nucleus. J Virol 80:5494-8
Luxton, G W Gant; Lee, Joy I-Hsuan; Haverlock-Moyns, Sarah et al. (2006) The pseudorabies virus VP1/2 tegument protein is required for intracellular capsid transport. J Virol 80:201-9

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