Expression, Inducers and Cellular Sources of the Chemokine MIG (CXCL 9), During Primary Herpes Simplex Virus Type-1 Infection of the Cornea

Abstract

Purpose: To investigate the production of monokine induced by gamma-interferon (MIG) during a primary Herpes simplex virus type 1 (HSV-1) infection of the cornea. We hypothesize that multiple CXCR3 ligands are involved in T cell recruitment during HSV-1 corneal infection and that neutrophils have the potential to contribute to their production.Materials and methods: Levels of MIG were evaluated in an in vivo murine model of HSV-1 corneal infection by quantitative ELISA. Cultured murine corneal fibroblast (MCF) cells and purified neutrophils were stimulated in vitro with IFN-γ and IL-1α to determine inducers of MIG. Cellular sources of MIG production in vivo were investigated via cellular depletion studies. Additionally, MIG production resulting from interaction between resident human corneal cells and neutrophils was evaluated in an ex vivo model of human corneal infection.Results: MIG was significantly elevated on days 2–6 and on day 8 following corneal infection. MCF and neutrophils secreted MIG in response to IFN-γ, but not IL-1α stimulation. Co-stimulation with IFN-γ and IL-1α induced a four-fold increase in MIG production by MCF. However, the same combination led to a three-fold decrease in MIG production by neutrophils. In vivo, a 52% reduction in MIG levels was observed in the neutrophil depleted host. In the human ex vivo model, MIG levels were significantly elevated in response to communication between HSV-1 infected corneal tissue and neutrophils.Conclusions: Here, we report the evidence for the production of MIG, a second CXCR3 ligand, during the primary immune response to HSV-1 corneal infection. Our results support the hypothesis that both neutrophils and resident corneal cells contribute to MIG production in vivo. However, neutrophils produce MIG in response to communication with HSV-1-infected resident corneal cells more efficiently than by direct interaction with virus. In addition, we found that MIG production by neutrophils and resident corneal cells was differentially regulated by IL-1α.