# HSV-1 reactivation and glaucomatous trabecular meshwork damage

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $191,045

## Abstract

Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma
and is due to damage to the trabecular meshwork (TM) leading to impaired aqueous humor outflow. We
have shown that toll-like receptor 4 (TLR4) is an important receptor involved in the development of ocular
hypertension and TM damage. Fibronectin extra domain A (FN-EDA) is a known damage associated
molecular pattern (DAMP) and endogenous ligand of TLR4. FN-EDA is produced because of tissue damage
and remodeling, leads to pathogenic TM damage, and is increased in the glaucomatous TM. Herpes simplex
virus 1 (HSV-1) is a ubiquitous human virus that establishes a lifelong latent infection. HSV- 1 is taken up by
peripheral nerve termini that innervate ocular structures, and the virus is retrograde transported to neurons
in the peripheral ganglia including the trigeminal ganglia (cornea) and ciliary ganglia (TM). After entering
neurons latency is established and latent HSV-1 genomes reactivate in response to external stressors,
including those that activate the TLR4 pathway. Importantly, recurrent ocular episodes of HSV-1 are a
leading cause of corneal blindness in the US and worldwide, yet little is known about the connection between
HSV-1 and other blinding eye diseases, such as glaucoma. It has been previously shown that HSV-1-
induced ocular inflammation leads to elevated aqueous proteins and inflammatory cells as well as damage
to TM cells, which can impede aqueous outflow and cause ocular hypertension. HSV-1 is a known cause of
secondary elevated IOP and glaucoma and is also associated with Glaucomatocyclic Crisis, a syndrome
characterized by recurrent attacks of ocular hypertension. However, it is unknown whether increased
intraocular pressure and DAMP-induced TM damage facilitate reactivation of latent HSV-1. We hypothesize
that the presence of DAMPs in the glaucomatous TM reactivate HSV-1 in the ciliary ganglia, leading to
recurrent HSV-1 reactivation and inflammation resulting in additional damage to the TM. Here we propose to
combine a novel in vitro human neuronal cell line capable of supporting HSV-1 latency and reactivation with
an in vivo rabbit ocular model of HSV-1 infection to determine if the presence of DAMPs in the TM result in
reactivation of latent HSV-1 leading to progressive damage to ocular structures. Specific aims 1 will
determine whether HSV-1 infection causes TM damage and DAMP production, and Specific aim 2 will
determine whether DAMP activated TLR4 signaling leads to HSV-1 reactivation in neurons. The overarching
goal of this project is to determine how HSV-1 might contribute to the pathogenesis associated with
glaucoma.

## Key facts

- **NIH application ID:** 10783757
- **Project number:** 5R21EY034295-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Colleen Mary McDowell
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $191,045
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783757

## Citation

> US National Institutes of Health, RePORTER application 10783757, HSV-1 reactivation and glaucomatous trabecular meshwork damage (5R21EY034295-02). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10783757. Licensed CC0.

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