Dissecting the pathogenic versus protective roles of IFN-γ and IL-17 in staphylococcal toxic shock syndrome and pneumonia using gene targeted HLA-DR3 transgenic mice

Abstract

Abstract The classical, adaptive T cell response to infectious agents is delayed and is antigen-specific. However, the superantigen (SAg) family of exotoxins, which are readily produced in vivo during Staphylococcus aureus infections, cause an immediate and non-specific activation of T cells, resulting in systemic elevation in many cytokines including IFN-γ and IL-17. While both IFN-γ and IL-17 are pro-inflammatory, they play distinct roles in mediating tissue injury and in immunity to infections. Therefore, to precisely delineate the roles of IFN-γ and IL-17 in immunopathology and immunity to diseases caused by S. aureus and its SAg, we first assessed the expression profiles of IFN-γ, IL-17 family members and their receptors in the spleens of HLA-DR3 transgenic mice challenged with a purified SAg using Illumina microarrays. The expression of ifng gene in spleens of HLA-DR3 transgenic mice was significantly higher than Il17a, Il17d and IL17f at all time-points tested (3, 6, 9, 24, 48 and 72 hrs, 3–4 mice per time point). Serum levels of these cytokines correlated with the gene expression data. Subsequently, HLA-DR3, HLA-DR3.IFN-γ−/− and HLA-DR3.IL-17−/− mice were generated and challenged with purified SAg or infected intratracheally with a SAg-producing strain of S. aureus. While both HLA-DR3 (mortality - 11/19) and HLA-DR3.IL-17−/− (mortality - 15/21) mice succumbed to SAg-induced toxic shock syndrome as well as pneumonia, HLA-DR.IFN-γ−/− mice (mortality - 1/11) were significantly protected (p<0.01) in both disease models. Bacterial loads were not different. In conclusion, our novel study using gene targeted humanized mice reveals that while both Th1 and Th17 cells are robustly activated by SAg, Th1 cells and IFN-γ play a lethal role.