ABSTRACT
Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK.
Subject(s)
Fas Ligand Protein/metabolism , Herpesvirus 1, Human , Keratitis, Herpetic/metabolism , Keratitis, Herpetic/virology , fas Receptor/metabolism , Animals , Antibodies, Viral/immunology , Cornea/immunology , Cornea/metabolism , Cornea/virology , Disease Models, Animal , Fas Ligand Protein/genetics , Gene Expression , Genome, Viral , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/immunology , Humans , Keratitis, Herpetic/genetics , Keratitis, Herpetic/immunology , Keratitis, Herpetic/mortality , Mice , Mice, Transgenic , Mutation , Protein Binding , Recurrence , Viral Load , Virus Activation/immunology , Virus Activation/radiation effects , Virus Shedding , fas Receptor/geneticsABSTRACT
PURPOSE: The present study was designed to test the therapeutic value of soluble FasL (sFasL) in an acute model of herpetic stromal keratitis (HSK) and, more importantly, a recurrent model of HSK using BALB/c, BALB-lpr, and National Institutes of Health (NIH) mice. METHODS: Mice were infected either acutely with the KOS strain of herpes simplex virus 1 (HSV-1) or latently with the McKrae strain of HSV-1. Acutely infected mice as well as ultraviolet-B (UV-B) reactivated mice (recurrent infection) were treated with sFasL, or soluble TNF-related apoptosis inducing ligand (sTRAIL), or BSA daily or 3 times/wk by using either a combination of subconjunctival injection and topical ointment, or with topical ointment alone. These mice then were evaluated for corneal opacity and neovascularization for 6 weeks. RESULTS: Following acute and recurrent HSV-1 infection, wild-type BALB/c mice treated with sFasL displayed significantly reduced incidence of corneal opacity and neovascularization compared to the control animals. However, BALB-lpr mice, which are deficient in Fas+ inflammatory cells, displayed no such differences in ocular disease, as expected. Latently infected NIH mice treated with sFasL displayed similar results. Flow cytometric analysis revealed that the corneal inflammatory infiltrate in those treated with sFasL was significantly less than in sTRAIL- or BSA-treated mice. Furthermore, corneas from sFasL-treated mice displayed relatively more cells undergoing apoptosis. CONCLUSIONS: This study provides evidence that sFasL treatment has potential therapeutic benefit in reducing inflammatory infiltrate and neovascularization in primary and recurrent forms of HSK, and that it does so by augmenting the restriction of Fas+ inflammatory cells mediated by membrane FasL.
Subject(s)
Corneal Stroma/virology , Fas Ligand Protein/pharmacology , Herpesvirus 1, Human , Keratitis, Herpetic/drug therapy , Acute Disease , Animals , Corneal Stroma/drug effects , Corneal Stroma/pathology , Disease Models, Animal , Keratitis, Herpetic/chemically induced , Keratitis, Herpetic/pathology , Mice , Mice, Inbred BALB C , RecurrenceABSTRACT
Herpetic stromal keratitis (HSK) is characterized by an inflammatory response that includes neutrophils, macrophages, NK cells, and T cells. The factors that are responsible for this inflammation are proinflammatory cytokines and chemokines. Many of these factors have been defined for primary disease, but relatively few have been investigated during recurrent HSK. The present study was designed to determine the role that two of these factors, IL-6 and CXCL1, play during recurrent HSK. Results clearly indicate that unlike primary disease, IL-6 plays no role in recurrent HSK. However, the presence of CXCL1 is required for recurrent HSK as evidenced by the lack of corneal disease in mice treated with anti-CXCL1 Ab. This was confirmed using mice lacking the primary receptor for CXCL1, CXCR2. Corneal disease in this strain was significantly reduced compared with wild-type C57BL/6 controls. Unexpectedly, lack of disease occurs even though CXCL1 knockout mice display increased viral shedding at the cornea. The primary mechanism that CXCL1 plays during disease is its ability to stimulate neutrophils to infiltrate the cornea following reactivation. This paper provides further evidence that primary HSK and recurrent HSK possess overlapping yet distinct disease mechanisms.
