title: Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis.
abstract: 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.
authors.affiliation: Immunology Research Centre, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
authors.forename: Aisling
authors.initials: A
authors.lastname: Dunne
authors.forename: Pádraig J
authors.initials: PJ
authors.lastname: Ross
authors.forename: Eva
authors.initials: E
authors.lastname: Pospisilova
authors.forename: Jiri
authors.initials: J
authors.lastname: Masin
authors.forename: Aoife
authors.initials: A
authors.lastname: Meaney
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Sutton
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Peter
authors.initials: P
authors.lastname: Sebo
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D001886:Bordetella pertussis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000382:microbiology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000502:physiology; D007442:Intubation, Intratracheal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012141:Respiratory Tract Infections / Q000201:enzymology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D037361:Adenylate Cyclase Toxin; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1