Inflammasome-dependent IFN-γ drives pathogenesis in Streptococcus pneumoniae meningitis.
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.
Sydney Medical School, University of Sydney, Camperdown, New South Wales 2050, Australia.
Andrew J
AJ
Mitchell
Belinda
B
Yau
James A
JA
McQuillan
Helen J
HJ
Ball
Lay Khoon
LK
Too
Arby
A
Abtin
Paul
P
Hertzog
Stephen L
SL
Leib
Cheryl A
CA
Jones
Sebastien K
SK
Gerega
Wolfgang
W
Weninger
Nicholas H
NH
Hunt
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D008586:Meningitis, Pneumococcal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D058847:Inflammasomes; D020382:Interleukin-18; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase