HSV-1 reactivation and glaucomatous trabecular meshwork damage

点击翻译按钮获取中文摘要

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.