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Pneumolysin Activates the NLRP3 Inflammasome and Promotes Proinflammatory Cytokines Independently of TLR4

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posted on 24.06.2013, 11:49 by Edel A. McNeela, Áine Burke, Daniel R. Neill, Cathy Baxter, Vitor E. Fernandes, Daniela Ferreira, Sarah Smeaton, Rana El-Rachkidy, Rachel M. McLoughlin, Andres Mori, Barry Moran, Katherine A. Fitzgerald, Jurg Tschopp, Virginie Pėtrilli, Peter W. Andrew, Aras Kadioglu, Ed C. Lavelle
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.

History

Citation

PLoS Pathogens, 2010, 6 (11), e1001191 (16)

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

PLoS Pathogens

Publisher

Public Library of Science

issn

1553-7366

eissn

1553-7374

Copyright date

2010

Available date

24/06/2013

Publisher version

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001191

Language

en