Ocular adenoviral infections occur in epidemics worldwide, and are associated with significant patient morbidity. Currently, there is no effective antiviral therapy, nor has there been an animal model in which to study the pathogenesis of ocular disease or to test new antivirals.
The specific aims of the current proposal are: 1) to begin the study of the pathogenesis of adenoviral ocular infection in our NZ rabbit ocular model. Specifically, to determine the molecular basis for differences in serotype virulence, and the mechanism of host range extension of Ad 5 in our successful model; and 2) to evaluate new antivirals as potential therapeutic agents in vitro and in the NZ rabbit ocular model. Preliminary ocular studies in 44 NZ rabbits suggested differences in adenovirus pathogenicity based on viral serotype: Ad 5 (productive infection), Ad 8 (abortive infection), and Ad 19 (no infection). A successful ocular model of adenovirus infection was developed in 32 NZ rabbits infected with Ad 5 McEwen, a clinical isolate, using a paired-eye design. Reproducible acute ocular infection was demonstrated with viral replication for 8 consecutive days. Peak ocular viral titers (103 pfu/ml) were achieved on day 3 p.i. and represented a two log increase (x100) over tivitis (24/32 eyes, 75 percent), and delayed onset of presumed immune-mediated clinical disease: blepharoconjunctivitis (21/32 eyes, 66 percent), iritis (29/32 eyes, 91 percent), corneal edema (32/32 eyes, 100 percent), and subepithelial corneal infiltrates (30/32 eyes, 94 percent). Preliminary in vitro antiviral studies with S-HMPHA and 2'-nor-cGMP demonstrated potent inhibitory activity against several human ocular serotypes: Ad 5, Ad 8, and Ad 19. The current proposal seeks to test these promising agents in our new in vivo rabbit ocular model. The applicant's long term goals are to achieve a better understanding of the molecular basis of the pathogenesis of adenoviral ocular infections, and to develop effective treatment to reduce patient suffering.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008227-02
Application #
3265440
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1991-05-01
Project End
1994-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Eye and Ear Institute of Pittsburgh
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kowalski, Regis P; Romanowski, Eric G; Mah, Francis S et al. (2010) Topical levofloxacin 1.5% overcomes in vitro resistance in rabbit keratitis models. Acta Ophthalmol 88:e120-5
Gordon, Y Jerold; Romanowski, Eric G; Shanks, Robert M Q et al. (2009) CAP37-derived antimicrobial peptides have in vitro antiviral activity against adenovirus and herpes simplex virus type 1. Curr Eye Res 34:241-9
Romanowski, Eric G; Yates, Kathleen A; Gordon, Y Jerold (2009) The in vitro and in vivo evaluation of ddC as a topical antiviral for ocular adenovirus infections. Invest Ophthalmol Vis Sci 50:5295-9
Nwanegbo, Edward C; Romanowski, Eric G; Gordon, Y Jerold et al. (2007) Efficacy of topical immunoglobulins against experimental adenoviral ocular infection. Invest Ophthalmol Vis Sci 48:4171-6
Romanowski, Eric G; Yates, Kathleen A; Teuchner, Barbara et al. (2006) N-chlorotaurine is an effective antiviral agent against adenovirus in vitro and in the Ad5/NZW rabbit ocular model. Invest Ophthalmol Vis Sci 47:2021-6
Gordon, Y Jerold; Romanowski, Eric G; McDermott, Alison M (2005) A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr Eye Res 30:505-15
Romanowski, Eric G; Pless, Patricia; Yates, Kathleen A et al. (2005) Topical cyclosporine A inhibits subepithelial immune infiltrates but also promotes viral shedding in experimental adenovirus models. Cornea 24:86-91
Harvey, Stephen A K; Romanowski, Eric G; Yates, Kathleen A et al. (2005) Adenovirus-directed ocular innate immunity: the role of conjunctival defensin-like chemokines (IP-10, I-TAC) and phagocytic human defensin-alpha. Invest Ophthalmol Vis Sci 46:3657-65
Kinchington, Paul R; Romanowski, Eric G; Jerold Gordon, Y (2005) Prospects for adenovirus antivirals. J Antimicrob Chemother 55:424-9
Gordon, Y Jerold; Huang, Ling C; Romanowski, Eric G et al. (2005) Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr Eye Res 30:385-94

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