Article: article from journal or magazin.
Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis.
Journal of Immunology
Inflammasome-mediated IL-1beta production is central to the innate immune defects that give rise to certain autoinflammatory diseases and may also be associated with the generation of IL-17-producing CD4(+) T (Th17) cells that mediate autoimmunity. However, the role of the inflammasome in driving adaptive immunity to infection has not been addressed. In this article, we demonstrate that inflammasome-mediated IL-1beta plays a critical role in promoting Ag-specific Th17 cells and in generating protective immunity against Bordetella pertussis infection. Using a murine respiratory challenge model, we demonstrated that the course of B. pertussis infection was significantly exacerbated in IL-1R type I-defective (IL-1RI(-/-)) mice. We found that adenylate cyclase toxin (CyaA), a key virulence factor secreted by B. pertussis, induced robust IL-1beta production by dendritic cells through activation of caspase-1 and the NALP3-containing inflammasome complex. Using mutant toxins, we demonstrate that CyaA-mediated activation of caspase-1 was not dependent on adenylate cyclase enzyme activity but was dependent on the pore-forming capacity of CyaA. In addition, CyaA promoted the induction of Ag-specific Th17 cells in wild-type but not IL-1RI(-/-) mice. Furthermore, the bacterial load was enhanced in IL-17-defective mice. Our findings demonstrate that CyaA, a virulence factor from B. pertussis, promotes innate IL-1beta production via activation of the NALP3 inflammasome and, thereby, polarizes T cell responses toward the Th17 subtype. In addition to its known role in subverting host immunity, our findings suggest that CyaA can promote IL-1beta-mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.
Adenylate Cyclase Toxin/physiology, Adenylate Cyclase Toxin/toxicity, Animals, Bordetella pertussis/immunology, CD4-Positive T-Lymphocytes/enzymology, CD4-Positive T-Lymphocytes/immunology, Carrier Proteins/metabolism, Caspase 1/metabolism, Cell Polarity/immunology, Cells, Cultured, Epitopes, T-Lymphocyte/immunology, Inflammation/enzymology, Inflammation/microbiology, Inflammation Mediators/metabolism, Inflammation Mediators/physiology, Interleukin-17/biosynthesis, Interleukin-17/deficiency, Interleukin-1beta/biosynthesis, Interleukin-1beta/physiology, Intubation, Intratracheal, Mice, Mice, Inbred C57BL, Mice, Knockout, Respiratory Tract Infections/enzymology, Respiratory Tract Infections/microbiology
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