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Title: Pneumolysin Activates the NLRP3 Inflammasome and Promotes Proinflammatory Cytokines Independently of TLR4
Authors: McNeela, Edel A.
Burke, Áine
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
Pėtrilli, Virginie
Andrew, Peter W.
Kadioglu, Aras
Lavelle, Ed C.
First Published: 11-Nov-2010
Publisher: Public Library of Science
Citation: PLoS Pathogens, 2010, 6 (11), e1001191 (16)
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.
DOI Link: 10.1371/journal.ppat.1001191
ISSN: 1553-7366
eISSN: 1553-7374
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright: © 2010 McNeela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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