Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4
Authors
McNeela, Edel A.Burke, Aine
Neill, Daniel R
Baxter, Cathy
Fernandes, Vitor E.
Ferreira, Daniela
Smeaton, Sarah
El-Rachkidy, Rana
McLoughlin, Rachel M.
Mori, Andres
Moran, Barry
Fitzgerald, Katherine A.
Tschopp, Jurg
Petrilli, Virginie
Andrew, Peter W.
Kadioglu, Aras
Lavelle, Ed C.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2010-11-19Keywords
AnimalsBacterial Proteins
Bone Marrow
Carrier Proteins
Cells, Cultured
Cytokines
Dendritic Cells
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Inflammation Mediators
Killer Cells, Natural
Lung
Lymphocyte Activation
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Pneumococcal Infections
Spleen
Streptococcus pneumoniae
Streptolysins
Toll-Like Receptor 4
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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-1beta, IL-1alpha and TNF-alpha by DC and enhanced cytokines including IL-17A and IFN-gamma by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-gamma are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-gamma and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1beta plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1beta 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.Source
PLoS Pathog. 2010 Nov 11;6(11):e1001191. Link to article on publisher's siteDOI
10.1371/journal.ppat.1001191Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34885PubMed ID
21085613Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1001191