Saturday, April 20, 2024
4/20/2024
Project Summary The corneal transparency is essential for normal vision. However, the recurrent episodes of herpes simplex virus-1 (HSV-1) infection of the cornea causes stromal keratitis (SK), a very painful and vision impairing chronic inflammatory disease. SK is a severe condition and the leading cause of infectious blindness in the US. The virus replication in the corneal epithelium and associated inflammation play a central role in SK progression. Current SK therapies such as corticosteroids and anti-virals are non-specific, partially effective, and cause severe ocular and systemic side effects. Therefore, there is an unmet need to develop novel immunotherapies to address deficiencies associated with current SK therapies. 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 chronic SK pathology. 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 SK progression. Macrophages (M¿s) play a central role in HSV-1 clearance through phagocytosis of infected epithelial cells and apoptotic neutrophils. Our preliminary data indicate that HSV-1 stimulates IL-27 production by M¿s. Further, we show that IL-27 is critical for limiting HSV-1 replication in the cornea, IFN-ß production, optimum induction of adaptive immune responses, and suppression of SK pathology. Moreover, we show that HSV-1 promotes M¿ metabolic reprogramming with significantly increased immune-responsive gene 1 (Irg1) expression. Irg1 is an enzyme that converts citrate to itaconate during the tricarboxylic acid (TCA) cycle. Itaconate is a mitochondrial metabolite produced by activated M¿s to regulate inflammatory and anti-viral responses. Our data show that IL-27 negatively regulates Irg1 expression in M¿s after HSV-1 infection. Thus, our central hypothesis is that IL-27 plays a dual anti-viral and anti-inflammatory role in SK progression through modulation of HSV-1-induced increased Irg1/itaconate metabolism in M¿s to promote type I IFNs-mediated protective responses. In this proposal, we will investigate the molecular mechanisms for IL-27-mediated immunoregulation of innate and adaptive immune responses during SK progression (Aim1) and elucidate the interplay of HSV-1-induced IL-27 and Irg1/itaconate metabolism in M¿s and role in SK progression (Aim 2). The successful completion of proposed studies will identify novel molecular mechanisms for HSV-1-induced M¿ metabolic reprogramming and the contribution of M¿-specific IL-27/Irg-1/itaconate in the induction of anti-viral versus inflammatory responses during SK. These studies will open the platform for developing novel, safe, and effective therapies targeting IL-27 and M¿ metabolism to suppress recurrent HSV-1 infection and SK progression.
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