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

PLoS Pathogens

Áine Burke¹  Andres Mori¹  Ed C. Lavelle¹  Edel A. McNeela¹  Cathy Baxter¹  Jurg Tschopp²  Virginie Pétrilli²  Sarah Smeaton³  Vitor E. Fernandes³  Rana El-Rachkidy³  Aras Kadioglu³  Daniela Ferreira³  Peter W. Andrew³  Daniel R. Neill³  Katherine A. Fitzgerald⁴  Barry Moran⁵  Rachel M. McLoughlin⁵ 

[1] Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland;Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom;Department of Medicine, University of Massachusetts, Worcester, Massachusetts, United States of America;School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland

关键词: Secretion;    Cytokines;    Pneumococcus;    T cells;    Toxins;    Inflammasomes;    Respiratory infections;    Pneumonia;   

DOI  :  10.1371/journal.ppat.1001191

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY