# IL-27-mediated immunoregulation in HSV-1-induced stromal keratitis > **NIH NIH R01** · AUBURN UNIVERSITY AT AUBURN · 2023 · $395,927 ## Abstract Project Summary Among ocular infections, recurrent herpes simplex virus-1 (HSV-1) infection causes immune cell infiltration and opacity in the cornea and triggers a severe immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK is a painful condition and one of the leading causes of infectious blindness in the United States and worldwide. Current HSK treatments, such as anti-virals combined with corticosteroids, are partially effective, and prolonged use causes severe local and systemic side effects. Further, the emergence of multi- drug-resistant HSV-1 strains in HSK patients is a major clinical challenge. Therefore, there is an unmet clinical need to develop safe and effective immunotherapies to treat HSK. The selective induction of a potent anti- viral state with minimal activation of inflammatory immune responses embodies a powerful means to treat patients with recurrent HSK. In this application, we propose one such approach targeting IL-27, an immunoregulatory cytokine, to induce endogenous anti-viral and anti-inflammatory responses after corneal HSV-1 infection to suppress HSK progression. Macrophages (Mϕs) play a central role in initiating and resolving inflammation during HSK progression. Intracellular dsDNA from HSV-1 is recognized by cyclic- GMP-AMP (cGAMP) synthase (cGAS) and activates the stimulator of interferon genes (STING) pathway to promote anti-viral immunity. HSV-1 infected Mϕs promote glycolysis with compensatory downregulation of the tricarboxylic acid (TCA) cycle. We observed that the TCA cycle in activated Mϕs is disrupted with increased immune-responsive gene 1 (Irg1) expression, an enzyme that converts citrate to itaconate. Itaconate is an immunoregulatory mitochondrial metabolite that can play both pro- and anti-viral roles. Our preliminary data suggest that ocular HSV-1 infection promotes Irg1 expression in the cornea and Mϕs to suppress anti-viral immunity through negative regulation of the cGAS-STING pathway. Apart from pathogens, cytokines regulate metabolism in Mϕs to modulate their effector functions. We show that HSV-1 induces IL- 27 expression in the cornea, and mice lacking the IL-27 receptor are highly susceptible to ocular HSV-1 infection with increased viral titers and HSK severity. We show that IL-27 attenuates HSV-1-induced glycolytic metabolism in Mϕs and suppresses Irg1 expression to stimulate IFN-β and limit inflammatory cytokine production. Based on these observations, we hypothesize that HSV-1 reprograms Mϕs to promote the Irg1 to evade cGAS-STING-mediated anti-HSV-1 responses (Aim 1) and IL-27 attenuates HSV-1-induced glycolytic metabolism in Mϕs to suppress inflammation and promote anti-viral immunity through inhibition of Irg1 to activate cGAS-STING pathway (Aim 2). The primary outcome of this study will be to uncover how HSV-1 regulates Mϕ metabolism to evade anti-viral responses during HSK progression. Our proposed IL-27-based approach will complement the current anti-viral and ... ## Key facts - **NIH application ID:** 10737119 - **Project number:** 1R01EY034495-01A1 - **Recipient organization:** AUBURN UNIVERSITY AT AUBURN - **Principal Investigator:** Amol Suryawanshi - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $395,927 - **Award type:** 1 - **Project period:** 2023-09-30 → 2024-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10737119 ## Citation > US National Institutes of Health, RePORTER application 10737119, IL-27-mediated immunoregulation in HSV-1-induced stromal keratitis (1R01EY034495-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10737119. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*