Role of IL-27 in HSV-1-induced Herpetic Stromal Keratitis

Abstract

Herpes Stromal Keratitis (HSK) results from ocular infection with Herpes simplex virus-1 (HSV-1) and is one of the leading causes of infectious blindness. After primary lytic infection in the facial region, the virus establishes life-long latency in the trigeminal ganglion (TG). The periodic reactivations from latency involve the cornea with clinically evident HSK usually as the consequence of repeated recurrences. HSK lesions are primarily orchestrated by neutrophils and functional subsets of T cells, which infiltrate the cornea in response to the infection. The HSV-1 replication and the inflammatory reaction in the cornea lead to permanent damage to the cornea and cause vision impairment. Currently, a combination of antivirals and corticosteroids are used to treat HSK. However, there are numerous challenges in the current treatment paradigm including antiviral-resistant strains, glaucoma, and epithelial toxicity, when used for prolonged periods. There is a dire need for alternate therapeutic strategies to treat HSK. Cytokines are critical for the activation and differentiation of effector immune cells during HSK. In this work, we show that interleukin (IL)-27, an immunoregulatory cytokine, is upregulated in macrophages during HSV-1 infection. IL-27 receptor knockout mice were more susceptible to HSV-1 infection and had more severe HSK lesions. IL-27 plays a critical role in the optimum induction of effector CD4+ T cell responses and limiting HSK progression. Further, IL-27 plays an antiviral role by regulating macrophage-mediated HSV-1 killing, and type-I interferon (IFN) response after HSV-1 infection. IL-27 is also critical for macrophage survival, antigen uptake, and the expression of costimulatory molecules involved in the optimum induction of effector T-cell responses. Our results indicate that IL-27 promotes endogenous antiviral and anti-inflammatory responses and represents a promising target for suppressing HSK progression. IFNs are the first line of host defense against HSV-1 infection. Type-I IFNs are majorly produced by the corneal epithelial cells and immune cells such as macrophages, and dendritic cells (DCs) that infiltrate the cornea following HSV-1 infection. However, HSV-1 has evolved strategies to evade the host response and promote viral replication. In this work, we identified that HSV-1 infection regulates macrophage metabolism by promoting glycolysis and oxidative phosphorylation (OXPHOS). This leads to mitochondrial membrane depolarization and an increase in mitochondrial oxidative stress. Further, HSV-1 infection promotes itaconate in macrophages which disrupts the Kreb’s cycle as well as suppresses the IFN response. Upon exogenous administration of itaconate derivative, there was a significant reduction in the type-I IFN response and IL-27 in macrophages. Further, the absence of IL-27 signaling in macrophages promotes IRG1 expression and disrupts mitochondrial function. Therefore, targeting the itaconate/IL-27 pathway could be a therapeutic strategy for combating ocular HSV-1 infection. This dissertation focuses on providing a comprehensive background on HSV-1 immunobiology and identifying potential therapeutic strategies for HSK. Since IL-27 has a dual anti-inflammatory and antiviral role in regulating HSK, we propose targeting IL-27 signaling for HSK management.