Research Spotlight

Research Spotlight: Sterile alpha and TIR motif containing 1 (SARM1) as a host factor that determines blinding viral keratitis

Anthony Sy. Leger, PhD In July, the St. Leger Laboratory received word that a five-year R01 grant will be imminently awarded to study the role that Sterile alpha and TIR motif containing 1 (SARM1) plays in herpes stromal keratitis (HSK), one of the most common causes of blindness due to infection in America. Specifically, the focus of this grant is on how SARM1 affects corneal nerves; however, the St. Leger Lab has also found that SARM1 modulates immune cells, which are known to play a role in HSK pathogenesis. By defining how SARM1 may influence viral keratitis, St. Leger hopes that the end result of this grant will open up possibilities to target SARM1 therapeutically to alleviate blinding ocular surface disease. Using a mouse model of HSK, Dr. Hongmin Yun (Research Assistant Professor in St. Leger’s Lab)—under the guidance of Dr. Robert Hendricks (UPitt—Professor Emeritus)—showed that sensory nerves are lost from the cornea during HSV-1 infection, which leads to a loss of blink reflex, desiccation stress, and severe keratitis. Yun found that this effect was primarily attributed to vascular endothelial growth factor (VEGF) disrupting the normal nerve architecture within the cornea. In 2020, Yun was able to use an FDA-approved therapy, bevacizumab, to inhibit VEGFinduced sensory nerve loss, which restored blink reflex and alleviated disease. With that, Drs. St. Leger and Yun wanted to identify other factors that may influence the outcome of disease. Recently, SARM1 has garnered a fair amount of interest in the field of neuroimmunology due to its role in causing neuronal axonal degradation. Because of this, many have hypothesized that SARM1 negatively influences disease outcomes in dementia-related diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the loss of neuronal connections within the brain. Conversely, in unpublished data, St. Leger and Yun found that SARM1 is beneficial after HSV-1 infection of the cornea. Specifically, SARM1 appears to repress the ingrowth of “unsensing” sympathetic nerves and limits the inflammatory nature of immune cells, which both negatively influence disease. This process allows sensory nerves to remain in the cornea, which encourages the preservation of the optically clear cornea. Now, with five years of funding, St. Leger and Yun are focused on understanding how SARM1 may be functioning within immune cells and sympathetic nerves. In preliminary studies, the team has found that SARM1 limits inflammatory profiles within immune cells that respond to the virus within several hours of initial infection. Further, it also appears that SARM1 may restrict the growth of pathogenic sympathetic nerves within the superior cervical ganglion (SCG). A problem with ocular HSV-1 infection is that the virus is never cleared from the host; it remains latent in neuronal cell bodies within ganglia. Upon viral reactivation from latency after periods of immune suppression, stress, or ultra violet light, live virus is deposited in the cornea, which induces an immune response that disrupts the corneal nerve architecture. Repeated reactivation events over the course of one’s lifetime can result significant loss of blink reflex, desiccation stress, corneal damage, and potential blindness. At the completion of this grant, the St. Leger Lab hopes to identify SARM1 as a target to augment during reactivation events to limit the exacerbation of disease and slow or reverse pathology.

Dr. St. Leger is an Assistant Professor of Ophthalmology and Immunology at the University of Pittsburgh School of Medicine. He is the Director of the Ocular Microbiome and Immunity Laboratory.