HSV can cause a variety of ocular diseases in humans ranging in severity from mild to sight- threatening. In addition, HSV causes cold sores, genital sores, and encephalitis. The lifecycle of HSV comprises an acute infection at mucosal sites such as the cornea during which all virus genes are expressed, and latency in neurons, during which gene expression is limited. Latency is a major hurdle for treatment of herpetic diseases, the majority of which result from reactivation from latency. The NEI's 2012 Strategic Plan therefore seeks to elucidate immunity to HSV during acute and latent infection. The over-arching goal of this project, now in its 20th year, is to study innate and adaptive immunity to HSV during all stages of pathogenesis.
Three specific aims are proposed. We will examine aspects of innate (IFN-driven) and adaptive (T cell- driven) immunity, in addition to xenophagy - an aspect of the autophagy pathway that is emerging as an important link between innate and adaptive immunity. We will examine the roles of these defense pathways, in conjunction with the HSV genes that counter them, in acute infection of the cornea and nervous system, and in latency and reactivation. Much of the work will be performed using an in vivo mouse corneal model, although some aspects will utilize a new in vitro system. The following hypotheses will be tested: ? The balance of IFN-driven innate immunity, and viral genes that dampen the IFN response determines the outcome of HSV corneal infection. Innate immunity is critical for protection of the cornea from infection.
This aim will further dissect the factors are important in recognition of the invading pathogen and generating an appropriate immune response. We will also study the impact of viral countering of the host response. ? HSV genes that thwart the host autophagy response also modulate the development of T cell immunity, thereby affecting HSV replication and pathogenesis. By controlling the autophagy/xenophagy response, we, and others have shown that HSV controls both direct intracellular degradation, and antigen presentation. Through creation and use of HSV recombinants altered in ability to modulate autophagy, in combination with mice lacking autophagy in their antigen presenting cells, we will determine the impact of host xenophagy on development of T cell immunity, pathogenesis, and immunopathology following HSV infection. ? Autophagy and innate immunity are critical host responses that promote the establishment and maintenance of HSV latency. We have shown that autophagy/xenophagy is especially important for protection of neurons from acute virus infection. We will use a new in vitro HSV latency model of adult sensory neurons to examine the role of xenophagy in the establishment and maintenance of latency. This proposal will thereby examine the host-pathogen interface not only through study of the roles of host defense against HSV, but also through study of how HSV counters host immunity. If successful, these aims will bring an improved understanding of host and viral factors involved in HSV pathogenesis.

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 leading of viral encephalitis. Treatments for HSV-related disease are very limited, no there is no vaccine. The goal of our work is to characterize HSV host and viral genes that are important in the determining the pathogenesis and outcome of infection using a mouse model. The successful outcome of this work will likely pave the way for new treatments and vaccines for therapy of herpes infections.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY009083-21
Application #
8503021
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
1992-01-09
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
21
Fiscal Year
2013
Total Cost
$405,000
Indirect Cost
$155,000
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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
Katzenell, Sarah; Leib, David A (2016) Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons. J Virol 90:4706-19
Rosato, Pamela C; Katzenell, Sarah; Pesola, Jean M et al. (2016) Neuronal IFN signaling is dispensable for the establishment of HSV-1 latency. Virology 497:323-7
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Parker, Zachary M; Murphy, Aisling A; Leib, David A (2015) Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1. J Virol 89:11080-91
Rosato, Pamela C; Leib, David A (2015) Neuronal Interferon Signaling Is Required for Protection against Herpes Simplex Virus Replication and Pathogenesis. PLoS Pathog 11:e1005028
Rosato, Pamela C; Leib, David A (2015) Neurons versus herpes simplex virus: the innate immune interactions that contribute to a host-pathogen standoff. Future Virol 10:699-714
Jiang, Yike; Yin, Xiaotang; Stuart, Patrick M et al. (2015) Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology. MBio 6:e01426-15
Torres, Iviana M; Patankar, Yash R; Shabaneh, Tamer B et al. (2014) Acidosis potentiates the host proinflammatory interleukin-1β response to Pseudomonas aeruginosa infection. Infect Immun 82:4689-97
Katzenell, Sarah; Chen, Yufei; Parker, Zachary M et al. (2014) The differential interferon responses of two strains of Stat1-deficient mice do not alter susceptibility to HSV-1 and VSV in vivo. Virology 450-451:350-4

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