# Novel Mechanisms in Adenoviral Ocular Pathogenesis

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2022 · $27,205

## Abstract

PROJECT SUMMARY
Conjunctivitis impacts approximately 6 million people annually in the United States, accounting for 1%
of all primary care office visits, and costing 430 million USD annually. Viruses are responsible for ~80%
of conjunctivitis cases, and human adenoviruses (HAdVs) are implicated in up to 65% of these. A
particularly severe cause of conjunctivitis, epidemic keratoconjunctivitis (EKC) is caused principally by
viruses within human adenovirus species D (HAdV-D), for example the highly virulent adenovirus type
37 (HAdV-D37). The clinical manifestations of EKC include severe membranous conjunctivitis and
epithelial keratitis, followed by delayed onset of multifocal subepithelial (stromal) corneal infiltrates. The
latter cause light sensitivity and reduced vision, and can persist or recur for months to years after the
acute infection, long after the virus is gone. We have shown in work published over the last 20+ years
that adenovirus binding to human corneal cells activates complex intracellular signaling events that
control subsequent cellular entry, intracellular trafficking of virions for delivery of viral DNA into cell
nuclei, virion assembly and viral replication, and proinflammatory gene expression by infected cells. In
this application, we extend our studies with new revelations on viral trafficking, new functions for a viral
structural protein, and new evidence for expression of a novel proinflammatory mediator by infected
corneal epithelial cells. The specific aims of this proposal are to test the hypotheses that 1) kinesin-1
and V-ATPase play previously unidentified roles in adenovirus trafficking, 2) adenoviral minor coat
protein IIIa promotes adenovirus replication, and 3) corneal epithelial cell HMGB1 promotes
inflammation in adenovirus keratitis. We will apply proteomic, siRNA, and imaging approaches to
determine final stages of virion uncoating in human corneal epithelial cells and human corneal
fibroblasts. A role for viral protein IIIa in nuclear transport of viral proteins for virion assembly will be
determined by use of deletion and point mutants of pIIIa through surface plasmon resonance, imaging,
PCR, and proteomics experiments. Finally, we will determine a role for human corneal epithelial cell
expression of the multi-potent molecule HMGB1 in the formation of subepithelial infiltrates in EKC.
These studies are designed to move us toward a more detailed understanding of adenoviral corneal
pathogenesis, in order to reach our goal of an information-based therapy to mitigate the morbidity of
adenovirus ocular infections.

## Key facts

- **NIH application ID:** 10487489
- **Project number:** 5R01EY021558-11
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** James Chodosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $27,205
- **Award type:** 5
- **Project period:** 2011-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487489

## Citation

> US National Institutes of Health, RePORTER application 10487489, Novel Mechanisms in Adenoviral Ocular Pathogenesis (5R01EY021558-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10487489. Licensed CC0.

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