The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia

Martin Witzenrath, Florence Pache, Daniel Lorenz, Uwe Koppe, Birgitt Gutbier, Christoph Tabeling, Katrin Reppe, Karolin Meixenberger, Anca Dorhoi, Jiangtao Ma, Ashleigh Holmes, George Trendelenburg, Markus M Heimesaat, Stefan Bereswill, Mark van der Linden, Jürg Tschopp, Timothy J Mitchell, Norbert Suttorp, Bastian Opitz

Research output: Contribution to journalArticlepeer-review

177 Citations (Scopus)

Abstract

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and sepsis. Pneumococci can be divided into >90 serotypes that show differences in the pathogenicity and invasiveness. We tested the hypotheses that the innate immune inflammasome pathway is involved in fighting pneumococcal pneumonia and that some invasive pneumococcal types are not recognized by this pathway. We show that human and murine mononuclear cells responded to S. pneumoniae expressing hemolytic pneumolysin by producing IL-1β. This IL-1β production depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Some serotype 1, serotype 8, and serotype 7F bacteria, which have previously been associated with increased invasiveness and with production of toxins with reduced hemolytic activity, or bacterial mutants lacking pneumolysin did not stimulate notable IL-1β production. We further found that NLRP3 was beneficial for mice during pneumonia caused by pneumococci expressing hemolytic pneumolysin and was involved in cytokine production and maintenance of the pulmonary microvascular barrier. Overall, the inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin but is not activated by clinically important pneumococcal sequence types causing invasive disease. The study indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system.

Original languageEnglish
Pages (from-to)434-40
Number of pages7
JournalJournal of Immunology
Volume187
Issue number1
DOIs
Publication statusPublished - 1 Jul 2011

Keywords

  • Animals
  • Bacterial Proteins
  • Bone Marrow Cells
  • Carrier Proteins
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Immunity, Innate
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88
  • Nod2 Signaling Adaptor Protein
  • Pneumonia, Pneumococcal
  • Signal Transduction
  • Streptolysins
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9

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