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Il-27-mediated immunoregulation in HSV-1 induced stromal keratitis

Award Number: R01EY034495
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Il-27-mediated immunoregulation in HSV-1 induced stromal keratitis - 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 immunosuppressive HSK therapies to increase their efficacy, thus lowering the risk of side effects.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $383,845 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Vision Research	000	4	4/2/2026	NON-COMPETING CONTINUATION	$383,845
														Subtotal = $383,845

Issue Date FY: 2025 ( Subtotal = $386,146 )
2025	2025	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Vision Research	001	3	4/4/2025	NON-COMPETING CONTINUATION	$386,146
2025	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Vision Research	000	2	4/2/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $386,146

Issue Date FY: 2024 ( Subtotal = $394,545 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Vision Research	001	2	8/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$394,545
2024	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Vision Research	000	1	8/8/2024	NEW	$0
														Subtotal = $394,545

Issue Date FY: 2023 ( Subtotal = $395,927 )
2023	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Vision Research	000	1	9/14/2023	NEW	$395,927
														Subtotal = $395,927

Grand Total All Awards = $1,560,463

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Il-27-mediated immunoregulation in HSV-1 induced stromal keratitis

Award Number: R01EY034495

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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