Wednesday, April 2, 2025
4/2/2025
Autophagic Regulation of Eye Interaction - Herpes simplex virus type-1 (HSV-1) provides a valuable tool for identifying new cellular mechanisms that safeguard the cornea and innervating sensory nerves. HSV-1 infections in the cornea can lead to epithelial damage, chronic inflammation, and impairment of sensory nerve fibers, ultimately resulting in blindness. In recent research, we investigated the role of the optineurin (OPTN) gene in HSV-1 infection and unexpectedly found an inverse correlation between OPTN expression and the severity of herpes stromal keratitis (HSK) in experimental mice. Our published findings also demonstrated that OPTN dysfunction leads to accelerated loss of central nervous system (CNS) neurons after HSV-1 eye infection. OPTN-/- animals show issues with the development of adaptive immune responses and deficiencies in autophagic degradation of HSV-1 proteins. Notably, OPTN, an autophagy receptor, is known for regulating the transport of ubiquitinated proteins and damaged mitochondria to autophagosomes for degradation. Our preliminary findings using OPTN-/- animals indicate that the loss of OPTN directly correlates with the loss of corneal nerve functions, underscoring its unrecognized significance in herpes neurotrophic keratitis (HNK) and other sensory nerve complications, such as dry eye disease (DED). Additionally, our data suggest a unique role for OPTN in promoting optimal MHC class II levels in response to HSV-1 infection in antigen-presenting cells, such as Dendritic Cells (DCs), which has the potential to explain the issues with compromised immunity in OPTN-/- animals. Based on our recently published and preliminary data, we propose a stimulating hypothesis that OPTN plays a central yet poorly understood role in mitigating the severity of herpetic eye disease. To deepen our understanding, we plan to comprehensively investigate the impact of OPTN on herpetic disease in the cornea. Our research will pursue three independent Specific Aims, conducting extensive in vitro and in vivo studies to assess the molecular mechanisms regulated by OPTN, particularly regarding viral degradation and homeostasis in HSV-1-infected cells, as well as OPTN's role in antigen presentation and its influence on the innate-adaptive immune axis. Additionally, we will utilize wildtype and OPTN-/- murine models of corneal infection to investigate OPTN's involvement in corneal sensitivity loss, studying its effects on corneal neurons and sensory nerve fiber damage. Our findings will generate new knowledge of how OPTN contributes to reducing ocular infection severity and enhancing antiviral immunity while preventing the loss of sensory neurons during infection. Moreover, our findings will have broader clinical implications for ocular infections in general. Similar to our results in experimental mice, the analysis of publicly available human transcriptomic data showed significant downregulation of OPTN in bacterial keratitis patients. Furthermore, this research may uncover new information on autophagic control of corneal health, and novel therapeutic strategies for herpetic eye diseases, with implications for neurodegenerative diseases in general.
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