One of the most exciting areas in biology is the nervous system and how it works. Viral infections of the nervous system have provided exceptional insight at many levels, from pathogenesis to basic biology. The mechanism(s) by which alpha herpesvirus infections spread into, within, and out of the nervous system are understood in principle, but not in any detail despite considerable effort. This unique biology leads to efficient host-to-host transmission and establishment of these viruses in their natural host populations with minimal pathogenesis. A long-term goal of my laboratory is to determine the molecular mechanisms by which neuroinvasive alpha-herpesviruses move in and out of the mammalian nervous system. These mechanisms will provide targets for manipulation that could substantially expand our understanding of infection transmission. Work in this renewal proposal continues to build on powerful imaging technology developed in the past funding period to reveal how herpes virion components move inside neurons and from neurons to non-neuronal cells in vitro and in vivo. We seek to identify and quantify critical events and potential bottlenecks in long distance transmission of infection from the peripheral nervous system (PNS) to peripheral epithelial cells. Experiments are divided among three aims all featuring light and video microscopy: Imaging individual virion egress events using multi-color TIRF microscopy;assaying axon-cell egress and spread events with chambered neurons, three color virus technology, and fast epifluorescence imaging;and imaging in vivo/ex vivo PRV invasion of the PNS at the single cell and single particle level. The technology and knowledge obtained from these studies have broad application. They enable a better understanding of herpesvirus cell biology at the single cell and particle level, provide insight into potential bottlenecks during hot-host transmission and have implications for intervention strategies. This technology and knowledge also will provide opportunities to develop enhanced viral tracers for understanding the organization and functional architecture of the nervous system.

Public Health Relevance

The proposed studies will advance understanding of alpha-herpesvirus infection, pathogenesis, and trans-neuronal spread of infection by providing an entirely new imaging-based perspective of basic virus biology. This perspective derives from imaging methods to identify and quantify events at the single cell and single particle level that reveal how individual virus particles leave axons to infect tissues and how neurons respond to viral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060699-07
Application #
8719184
Study Section
Virology - A Study Section (VIRA)
Program Officer
Wong, May
Project Start
2007-12-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
$350,830
Indirect Cost
$134,268
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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; 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
Harris, Greg M; Madigan, Nicolas N; Lancaster, Karen Z et al. (2016) Nerve Guidance by a Decellularized Fibroblast Extracellular Matrix. Matrix Biol :
Hogue, Ian B; Scherer, Julian; Enquist, Lynn W (2016) Exocytosis of Alphaherpesvirus Virions, Light Particles, and Glycoproteins Uses Constitutive Secretory Mechanisms. MBio 7:
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
Bosse, Jens B; Hogue, Ian B; Feric, Marina et al. (2015) Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion. Proc Natl Acad Sci U S A 112:E5725-33
Koyuncu, Orkide O; Song, Ren; Greco, Todd M et al. (2015) The number of alphaherpesvirus particles infecting axons and the axonal protein repertoire determines the outcome of neuronal infection. MBio 6:
Kratchmarov, R; Enquist, L W; Taylor, M P (2015) Us9-Independent Axonal Sorting and Transport of the Pseudorabies Virus Glycoprotein gM. J Virol 89:6511-4
Hogue, Ian B; Bosse, Jens B; Engel, Esteban A et al. (2015) Fluorescent Protein Approaches in Alpha Herpesvirus Research. Viruses 7:5933-61
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

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