zed from abstract) Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in the US, with more that 200,000 cases per year. HSV can cause a variety of ocular diseases in humans ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. In addition, HSV commonly causes cold sores, genital sores, and is a leading cause of viral encephalitis. The life cycles of HSV and other neurotropic herpesviruses are characterized by a lytic phase of infection at peripheral sites such as the cornea, and skin during which all virus genes are expressed, and a latent phase of infection in neurons, during which gene expression is extremely limited. Latency represents a lifelong source of virus which can reactivate periodically causing severe ocular and other mucocutaneous damage, and the ability to establish lifelong latency renders HSV resistant to cure. The unique regulatory switch between lytic and latent infection is poorly understood. The broad goals of this proposal are to elucidate host and viral factors involved in the various stages of latency. To this end, recombinant viruses will be created with lesions in DNA replication and latency-related genes are tested in a mouse ocular model for their ability to establish and reactivate from latency in mice. These studies will be performed in conjunction with knockout mice with lesions in host genes such as interferons, which may play key roles in controlling HSV infection. This will allow the elucidation of the possible interplay between host and viral genes. In addition, the PI will engineer a transgenic mouse line which will allow us to specifically target viral genes for deletion during latency in the mouse. Viruses will therefore be wild-type during infection, but genetically altered during latency. This entirely novel approach to the field of herpes pathogenesis will allow us to dissect the precise roles for certain viral genes during the stages of the life cycle of the virus. A better understanding of both viral and host factors and their interplay in HSV pathogenesis will allow further insight into the mechanisms by which HSV can persist for the lifetime of its host and indicate novel therapeutic approaches and targets for control of this blinding disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY009083-11S1
Application #
6801177
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Shen, Grace L
Project Start
1992-01-09
Project End
2004-03-31
Budget Start
2002-07-01
Budget End
2004-03-31
Support Year
11
Fiscal Year
2003
Total Cost
$131,877
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cabrera, Jorge Ruben; Charron, Audra J; Leib, David A (2018) Neuronal subtype determines HSV-1 Latency-Associated-Transcript (LAT) promoter activity during latency. J Virol :
Jiang, Yike; Leib, David (2017) Preventing neonatal herpes infections through maternal immunization. Future Virol 12:709-711
Enquist, Lynn W; Leib, David A (2017) Intrinsic and Innate Defenses of Neurons: Détente with the Herpesviruses. J Virol 91:
Katzenell, Sarah; Cabrera, Jorge R; North, Brian J et al. (2017) Isolation, Purification, and Culture of Primary Murine Sensory Neurons. Methods Mol Biol 1656:229-251
Jiang, Yike; Patel, Chaya D; Manivanh, Richard et al. (2017) Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease. MBio 8:
Manivanh, Richard; Mehrbach, Jesse; Knipe, David M et al. (2017) Role of Herpes Simplex Virus 1 ?34.5 in the Regulation of IRF3 Signaling. J Virol 91:
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Parker, Zachary M; Pasieka, Tracy Jo; Parker, George A et al. (2016) Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure. J Virol 90:10789-10799
Rosato, Pamela C; Katzenell, Sarah; Pesola, Jean M et al. (2016) Neuronal IFN signaling is dispensable for the establishment of HSV-1 latency. Virology 497:323-327
Katzenell, Sarah; Leib, David A (2016) Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons. J Virol 90:4706-4719

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