Vestibular neuritis is the syndrome of acute onset, prolonged vertigo of peripheral origin. Vestibular neuritis is hypothesized to be the result of infection of the vestibular ganglion neurons (VGN) with a neurotrophic virus;and herpes simplex virus-1 (HSV-1) has been identified as a likely etiologic agent. We propose to study the role of HSV-I in vestibular neuritis by developing a murine cell culture system of HSV-1 infection and latency. Using HSV-1 virus with a green fluorescent protein (GFP) fusion to the US11 protein, we have infected dissociated VGNs harvested from postnatal rats, prevented this infection with acyclovir, and established a quiescent viral infection. In cultured cervical sympathetic ganglia, nerve growth factor (NGF) is necessary for maintenance of the latent state, and withdrawal of NGF from cell culture media results in loss of latency and a lytic infection. In VGNs, NGF and its high affinity receptor, TrkA, are not expressed. Therefore, we hypothesize that withdrawal of other neurotrophins (either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT3), whose Trk receptors are expressed in VGNs) leads to viral reactivation, and that these effects are independent from the neurotrophins'prosurvival effects. In latently infected VGNs, we have shown that application of K252a, a generalized Trk inhibitor, triggers viral reactivation, and we propose to further study this phenomenon and its intracellular efforts. This study will improve our understanding of the basic processes involved in HSV-1 mediated infections of VGNs, and provide future therapeutic targets for limiting acute infection. Further studies in this system will examine the effects of transactivation of Trk receptors on latency. Trk receptors are known to be transact!vated by other compounds which activate them on a slower time course than neurotrophins. Identification of these compounds could provide less toxic substitutes for neurotrophins, which could be taken systemically by patients at the onset of vestibular neuritis, thereby limiting the severity and duration of the acute syndrome.

Public Health Relevance

Vestibular neuritis is thought to result from the infection of the nerves of the peripheral balance sytem with herpes simplex 1. This study will examine the role of neural growth factors in preventing active herpes simplex 1 virus replication in the nerves of the balance system, with the goal of understanding this process and finding drugs that perform similar functions to limit active viral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DC009288-04
Application #
8306241
Study Section
Communication Disorders Review Committee (CDRC)
Program Officer
Sklare, Dan
Project Start
2009-09-01
Project End
2013-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$174,207
Indirect Cost
$12,795
Name
New York University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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