Herpes simplex virus type-1 (HSV-1) is the prototypic member of the Herpesviridae, with ~90% seroprevalence in adults. HSV causes cold sores, genital sores, and is the leading cause of viral encephalitis. HSV also causes ocular diseases ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. The ability of HSV to establish latency renders it resistant to cure and represents a major hurdle in the prevention of herpetic diseases, the majority of which result from recrudescence of the virus from this latent state. In accordance with this significant clinical problem and this proposal, the NEI's August 2012 Strategic Plan seeks to elucidate innate and adaptive immune responses in the cornea, and to develop vaccines and treatments for HSV-induced keratitis. The over-arching goal of this project, now in its 24th year, is to study innate and adaptive immunity to HSV during all stages of pathogenesis. Our central hypothesis is that innate immunity, and the autophagy pathway (which acts in both innate and adaptive immunity) act in a compartment-specific fashion to control HSV replication and disease. We further hypothesize that pharmacological modulation of innate immunity and autophagy will result in significant clinical benefit and improved resolution of infection and disease. In this competing continuation we will continue to study the interplay of host immunity and viral immunomodulatory genes in the determination of the outcome of HSV acute and latent infections. Our overall approach will be to examine acute infection, establishment, and reactivation of latency of HSV in a murine corneal model. We will use mouse strains deficient in selected pathways of host immunity in combination with HSV recombinants lacking selected immunomodulatory genes. On the virus side we will focus on HSV ?34.5 and ICP0 which are critical and versatile virulence determinants that counter many aspects of the innate response. On the host side we will focus on the tissue-specific IFN responses that serve to control virus infection. Using mouse and HSV genetics simultaneously provides a synergistic approach to address our hypotheses, advance our understanding of HSV pathogenesis and develop novel therapies. If successful, this project will elucidate the molecular and cellular basis of a complex and clinically significant host-pathogen interface, and also test 2 new candidate therapeutic approaches that were identified during the previous funding cycle. The impact of this project will therefore stem from identification of novel therapeutic paths for treatment of HSV, and from performance of proof-of-principle experiments for novel therapies against HSV ocular disease. More generally, this work will impact our overall understanding of fundamental mechanisms that promote the lifelong persistence of this ubiquitous and significant ocular pathogen.

Public Health Relevance

Herpes simplex virus (HSV) is a leading cause of non-traumatic blindness in developed countries and the causative agent of cold sores, genital sores, and a common cause of viral encephalitis. Treatments for HSV- related ocular disease are limited, and there is no vaccine. The goal of our work is to characterize host and HSV genes that are important in the determining the outcome of infection, and test new treatments for therapy of herpes infections.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009083-26
Application #
9616264
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
1992-01-09
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
26
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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: D├ętente 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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