Viruses of the family Herpesviridae, including herpes simplex types 1(HSV1) and 2, varicella zoster virus, cytomegalovirus, and Epstein-Barr Virus are complex enveloped viruses containing linear double-stranded DNA. As a group, they are responsible for a large number of serious human ailments. In its natural host, the adult human, the cold virus HSV1 primarily infects oral mucosal epithelium, followed by infection of sensory neurons innervating that mucosa. HSV1, as with all herpesviruses, is capable of achieving latency, and can be reactivated at a later time. Though relatively rare, HSV1 can also be the primary cause of the more serious herpes simplex encephalitis, as well as systemic disseminated infections. Demonstrating increased risk of the more serious sequelae of HSV1 infection is the portion of the population that is relatively immunosuppressed (neonates, transplant patients, or those with immune-suppressive disorders). It has been well established that ocular herpetic keratitis, HSV1 infection of the eye (approximately 300,000 cases diagnosed yearly) is, after trauma, the most common cause of corneal blindness in this country. Clearly, the multiple deleterious effects of HSV1 infection thus motivate us to attempt a better understanding of host cell responses to viral infection. The targeted intracellular transport of HSV-1 is essential for transmission of virus from an infected cell to its neighbor. The synaptic connections of the infected sensory neuron (which has axons that end in the periphery and central nervous system), and the ability of these viruses to be transferred from one neuron to its synaptically linked neighbor, provide a unique route by which virus can be presented the CNS. The mechanisms by which these neurotropic viruses accomplish that intracellular movement are thus of considerable interest not only to those investigating viral pathogenesis in the central nervous system, but also to those interested in the mechanisms of basic cellular targeting and transport of endogenous macromolecular complexes. The goal of this project is to elucidate mechanisms used by HSV-1 to accomplish targetted transport from its assembly site in the neuronal cell nucleus, through the cytoplasm to the plasma membrane. We first would like to establish definitively whether viral transport depends on the presence of the microtubule cytoskeleton and microtuble-dependent motor proteins. We would like to further investigate the biological form assumed by the virus during its targetted anterograde transport. Finally, we plan to investigate host cell macromolecules that may be recruited by the virus as well as viral proteins involved in that movement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038246-03
Application #
6540044
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Nunn, Michael
Project Start
2000-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$243,750
Indirect Cost
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Xie, Jiansong; Chiang, Lilian; Contreras, Janette et al. (2006) Novel fiber-dependent entry mechanism for adenovirus serotype 5 in lacrimal acini. J Virol 80:11833-51
da Costa, Silvia R; Wu, Kaijin; Veigh, Michelle Mac et al. (2006) Male NOD mouse external lacrimal glands exhibit profound changes in the exocytotic pathway early in postnatal development. Exp Eye Res 82:33-45
Wu, Kaijin; Jerdeva, Galina V; da Costa, Silvia R et al. (2006) Molecular mechanisms of lacrimal acinar secretory vesicle exocytosis. Exp Eye Res 83:84-96
Jerdeva, Galina V; Wu, Kaijin; Yarber, Francie A et al. (2005) Actin and non-muscle myosin II facilitate apical exocytosis of tear proteins in rabbit lacrimal acinar epithelial cells. J Cell Sci 118:4797-812
Wang, Y; Xie, J; Yarber, F A et al. (2004) Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland. Gene Ther 11:970-81
da Costa, Silvia R; Okamoto, Curtis T; Hamm-Alvarez, Sarah F (2003) Actin microfilaments et al.--the many components, effectors and regulators of epithelial cell endocytosis. Adv Drug Deliv Rev 55:1359-83
Hamm-Alvarez, Sarah F; Xie, Jiansong; Wang, Yanru et al. (2003) Modulation of secretory functions in epithelia by adenovirus capsid proteins. J Control Release 93:129-40
Wang, Yanru; Jerdeva, Galina; Yarber, Francie A et al. (2003) Cytoplasmic dynein participates in apically targeted stimulated secretory traffic in primary rabbit lacrimal acinar epithelial cells. J Cell Sci 116:2051-65
Da Costa, Silvia R; Sou, Eunbyul; Xie, Jiansong et al. (2003) Impairing actin filament or syndapin functions promotes accumulation of clathrin-coated vesicles at the apical plasma membrane of acinar epithelial cells. Mol Biol Cell 14:4397-413
Garner, Judy A (2003) Herpes simplex virion entry into and intracellular transport within mammalian cells. Adv Drug Deliv Rev 55:1497-513