Inflammasome-dependent IFN-γ drives pathogenesis in Streptococcus pneumoniae meningitis

Mitchell, Andrew J.; Yau, Belinda; McQuillan, James A; Ball, Helen J.; Too, Lay Khoon; Abtin, Arby; Hertzog, Paul; Leib, Stephen L.; Jones, Cheryl A.; Gerega, Sebastien K.; Weninger, Wolfgang; Hunt, Nicholas H. (2012). Inflammasome-dependent IFN-γ drives pathogenesis in Streptococcus pneumoniae meningitis. Journal of immunology, 189(10), pp. 4970-80. Bethesda, Md.: American Association of Immunologists 10.4049/jimmunol.1201687

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The pathology associated with Streptococcus pneumoniae meningitis results largely from activation of immune-associated pathways. We systematically investigated the production of IFN subtypes, as well as their influence on pathology, in a mouse model of S. pneumoniae meningitis. Despite the occurrence of a mixed IFN type I/II gene signature, no evidence for production or involvement of type I IFNs in disease progression was found. In contrast, type II IFN (IFN-γ) was strongly induced, and IFN-γ(-/-) mice were significantly protected from severe disease. Using intracellular cytokine staining and targeted cell-depletion approaches, NK cells were found to be the dominant source of IFN-γ. Furthermore, production of IFN-γ was found to be dependent upon ASC and IL-18, indicating that an ASC-dependent inflammasome pathway was responsible for mediating IFN-γ induction. The influence of IFN-γ gene deletion on a range of processes known to be involved in bacterial meningitis pathogenesis was examined. Although neutrophil numbers in the brain were similar in infected wild-type and IFN-γ(-/-) mice, both monocyte recruitment and CCL2 production were less in infected IFN-γ(-/-) mice compared with infected wild-type controls. Additionally, gene expression of NO synthase was strongly diminished in infected IFN-γ(-/-) mice compared with infected controls. Finally, bacterial clearance was enhanced in IFN-γ(-/-) mice, although the underlying mechanism remains unclear. Together, these data suggest that inflammasome-dependent IFN-γ contributes via multiple pathways to pathology during S. pneumoniae meningitis.

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