Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in developed countries, with more than 200,000 cases per year in the USA. 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 in neurons, during which gene expression is extremely limited. Latency represents a lifelong source of virus which reactivates periodically causing severe ocular and other damage. The ability of HSV to establish lifelong latency renders it resistant to cure and represents a major hurdle in the prevention of herpetic diseases, the majority of which result from reactivation from latency. Xenophagy is an important PKR-dependent host defense mechanism against chronic intracellular pathogens. It is a subset of the constitutive cellular process known as autophagy (self-eating), in which cytoplasmic components are sequestered and degraded by the lysosome to generate metabolic precursors, to remove damaged organelles and altered intracellular components. If the autophagic vacuole also engulfs and destroys invading pathogens, the process is known as xenophagy. Typical of many microbial countermeasures against innate immunity, xenophagy is either inhibited by the invading pathogen, or alternatively exploited to enhance its replication cycle. The processes of autophagy and xenophagy and their alteration by microbes is therefore another component of the cat-and-mouse game of microbial pathogenesis and host-pathogen interactions. A better understanding of these autophagic/xenophagic pathways could lead to a whole new class of antiviral therapies, designed to augment the xenophagic degradation of otherwise hard-to-treat intracellular pathogens, or to deny certain pathogens access to the autophagic machinery which serves to promote their replication. Three important aspects of the pathogenesis of HSV will be studied in this application. First, the role of xenophagy will be determined in several stages in the pathogenesis of HSV-1. Second, viral genes that subvert the host innate xenophagy and interferon (IFN)-mediated antiviral responses will be studied. Third, the role of this subversion will be studied in pathogenesis in the cornea and other tissues critical for HSV pathogenesis. The interplay of viral and host factors at various stages in the virus lifecycle remains poorly understood. A better understanding, at the molecular level, of factors involved in HSV pathogenesis is in accordance with stated research goals of the December 2006 National Plan for Eye and Vision Research. Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in developed countries, with more than 200,000 cases per year in the USA. In addition, HSV commonly causes cold sores, genital sores, and is a leading cause of viral encephalitis. A better understanding, at the molecular level, of factors involved in HSV pathogenesis will lead to improved therapies for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009083-20
Application #
8323419
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1992-01-09
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
20
Fiscal Year
2012
Total Cost
$375,408
Indirect Cost
$137,808
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Rosato, Pamela C; Leib, David A (2014) Intrinsic innate immunity fails to control herpes simplex virus and vesicular stomatitis virus replication in sensory neurons and fibroblasts. J Virol 88:9991-10001
Torres, Iviana M; Patankar, Yash R; Shabaneh, Tamer B et al. (2014) Acidosis potentiates the host proinflammatory interleukin-1? 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
Murphy, Aisling A; Rosato, Pamela C; Parker, Zachary M et al. (2013) Synergistic control of herpes simplex virus pathogenesis by IRF-3, and IRF-7 revealed through non-invasive bioluminescence imaging. Virology 444:71-9
Morris, Jessica E; Zobell, Stephanie; Yin, Xiao-Tang et al. (2012) Mice with mutations in Fas and Fas ligand demonstrate increased herpetic stromal keratitis following corneal infection with HSV-1. J Immunol 188:793-9
Pasieka, Tracy Jo; Collins, Lynne; O'Connor, Megan A et al. (2011) Bioluminescent imaging reveals divergent viral pathogenesis in two strains of Stat1-deficient mice, and in ?ß? interferon receptor-deficient mice. PLoS One 6:e24018
Menachery, Vineet D; Pasieka, Tracy Jo; Leib, David A (2010) Interferon regulatory factor 3-dependent pathways are critical for control of herpes simplex virus type 1 central nervous system infection. J Virol 84:9685-94
Pasieka, Tracy Jo; Cilloniz, Cristian; Lu, Betty et al. (2009) Host responses to wild-type and attenuated herpes simplex virus infection in the absence of Stat1. J Virol 83:2075-87
English, Luc; Chemali, Magali; Duron, Johanne et al. (2009) Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10:480-7
Menachery, Vineet D; Leib, David A (2009) Control of herpes simplex virus replication is mediated through an interferon regulatory factor 3-dependent pathway. J Virol 83:12399-406

Showing the most recent 10 out of 39 publications