title: Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4.
abstract: Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1β, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1β plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1β secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system.
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Edel A
authors.initials: EA
authors.lastname: McNeela
authors.forename: Aine
authors.initials: A
authors.lastname: Burke
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Neill
authors.forename: Cathy
authors.initials: C
authors.lastname: Baxter
authors.forename: Vitor E
authors.initials: VE
authors.lastname: Fernandes
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferreira
authors.forename: Sarah
authors.initials: S
authors.lastname: Smeaton
authors.forename: Rana
authors.initials: R
authors.lastname: El-Rachkidy
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: Andres
authors.initials: A
authors.lastname: Mori
authors.forename: Barry
authors.initials: B
authors.lastname: Moran
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Virginie
authors.initials: V
authors.lastname: Pétrilli
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrew
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018836:Inflammation Mediators / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011008:Pneumococcal Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity*; D013301:Streptolysins / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D013301:Streptolysins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C032290:plY protein, Streptococcus pneumoniae