Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Abstract

Inflammasome-mediated IL-1β 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-1β 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-1β 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-1β 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-1β–mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.

Antigen Targeting to CD11b+ Dendritic Cells in Association with TLR4/TRIF Signaling Promotes Strong CD8+ T Cell Responses

“…This finding is in accordance with the pattern of immune responses induced by CyaA, which activates both Th1-polarized CD4 + T cells and CTL responses (3,4). In agreement with our results, it recently has been reported that CyaA induced robust IL-1 production by DCs through the activation of caspase-1 and the NALP3-containing inflammasome complex (27). Although it has been shown that IL-1 and inflammasome could be important factors in the induction of T cell responses (23,28), the capacity of CyaA-OVA to trigger CTL responses was not affected in mice deficient in IL-1R or inflammasome components, clearly demonstrating that IL-1b and the inflammasome were not involved in the induction of the CTL response by the CyaA vector.…”

Escherichia coliHeat-Labile Enterotoxin Promotes Protective Th17 Responses against Infection by Driving Innate IL-1 and IL-23 Production

“…10C). Control nonimmunized Il17 2/2 mice had a higher bacterial burden than WT mice, which is consistent with the role of IL-17 in natural and whole-cell vaccine-induced immunity to B. pertussis (31,34). Immunization of WT mice, with Pa and LT as the adjuvant, significantly reduced the bacterial burden in the lungs of infected mice at day 5, with almost undetectable CFU by day 10.…”

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

“…Indeed, unlike several PRR, the NLR protein family senses microbial molecules intracellularly in the cytosol [42][43][44][45][46]. This mechanism has been described for some viral and bacterial proteins [47][48][49] and for some adjuvants such as aluminum salts [39]. Since the inhibition of Sap internalization via the clathrin-dependent pathway results in a consistent inhibition of IL-1β and IL-18, it can be concluded that Saps must reach the cytoplasmic compartment to induce inflammasome activation.…”