The most common cause of infectious corneal blindness in humans in the developed world is herpes simplex virus induced keratitis. The available evidence indicates that HSV initiates and produces this corneal inflammatory disease. The pathogenesis of herpes stromal keratitis, requires that HSV-1 be maintained as a latent infection in the ophthalmic sensory neurons of the trigeminal ganglia and that it be periodically reactivated. The reactivated virus can either contribute to the corneal inflammatory disease or infect new hosts. the underlying basis of herpetic corneal disease is latent neuronal infection by HSV-1. The stimuli which cause reactivation of HSV usually involved changes in the physiology of the host cell. This coupled with a failure to demonstrate viral genes that control the latent and reactivated viral genome, leads to the hypothesis that neuronal transcriptional proteins control this process by activating or repressing viral immediate early (IE) gene expression. No suitable model for studying the regulation of HSV-1 latency exists in cultured cells. The application of transgenic technology offers a powerful way to test whether host transcriptional proteins control latent HSV infection of sensory neurons. The experiments described in this proposal are intended to delineate the underlying mechanism by which the virus is regulated by host cells during latent and reactivated infections. An understanding of this mechanism should lead to design of strategies or prevent HSV induced corneal disease. The objectives of these studies are: 1) Establish whether host transcriptional proteins can regulate HSV IE genes in neurons in vivo and whether viral IE genes can be regulated in a way that would be appropriate for controlling latent and reactivated infections. 2) Determine whether inhibition or stimulation of viral Ie gene expression will result in alteration of the ability of HSV to establish a latent infection and reactivate. 3)Determine whether host transcriptional regulatory proteins can modulate latent and reactivated HSV infections of sensory ganglia in tansgenic mouse models.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011855-05
Application #
6384705
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1997-08-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2003-07-31
Support Year
5
Fiscal Year
2001
Total Cost
$138,268
Indirect Cost
Name
University of Missouri-Columbia
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211