Abstract
Purpose :
The selective induction of a robust antiviral state with minimal activation of pro-inflammatory immune responses embodies a powerful means to treat patients with recurrent corneal HSV infection-induced stromal keratitis (SK). Accordingly, regulating innate antiviral type I (IFN-α/β) and type III (IFN-λ) interferon responses represent a promising therapeutic approach for SK patients. Several past studies have characterized the antiviral and pro-inflammatory roles of type I interferons during corneal HSV infection. However, the relative contribution of IFN-λ, a frontline antiviral and anti-inflammatory cytokine at epithelial surfaces, during corneal HSV infection is yet to be defined.
Methods :
C57BL/6 mice cornea were infected with HSV. HSV infected were collected on day 1, 2 and 3 post infection (pi) for relative gene expression of interferon and stimulated genes (ISGs). Further, HSV infected mice were topically treated with recombinant IFN-λ (100 ng/eye) twice a day from day 1 to 5 pi. The severity of SK progression was scored on day 8, 11 and 14 pi. On day 15 cornea, lymph nodes and spleen were analyzed for neutrophils, macrophages, effector and regulatory T cell responses. Finally, in vivo and ex vivo experiments were performed to characterize the IFN-λ-mediated regulation of neutrophil biology during SK pathogenesis.
Results :
Ocular HSV infection significantly induced IFN-α, INF-λ and MX-1 production during early phase corneal HSV infection. The relative expression of INF-λ was higher compared to IFN-α, indicating the dominant role of INF-λ at corneal mucosa during HSV infection. Further, exogenous administration of rIFN-λ during SK progression significantly suppressed SK pathogenesis and influx of neutrophils and pro-inflammatory Th1 cells. Mechanistically, topical rIFN-λ treatment suppressed early viral replication, regulated neutrophil migration and effector functions at the site of viral replication and inflammation.
Conclusions :
Our data indicates that corneal HSV infection induces both type I and type III interferon responses. The normal progression of SK in HSV infected mice indicate insufficient IFN-λ-mediated anti-inflammatory activity. The amelioration of SK pathology after exogenous rIFN-l topical treatment indicate that simultaneous targeting of antiviral and anti-inflammatory responses represents a promising therapeutic approach to treat SK patients.
This is a 2020 ARVO Annual Meeting abstract.