title: The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia.
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.
authors.affiliation: Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, Charité University Medicine Berlin, 13353 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Florence
authors.initials: F
authors.lastname: Pache
authors.forename: Daniel
authors.initials: D
authors.lastname: Lorenz
authors.forename: Uwe
authors.initials: U
authors.lastname: Koppe
authors.forename: Birgitt
authors.initials: B
authors.lastname: Gutbier
authors.forename: Christoph
authors.initials: C
authors.lastname: Tabeling
authors.forename: Katrin
authors.initials: K
authors.lastname: Reppe
authors.forename: Karolin
authors.initials: K
authors.lastname: Meixenberger
authors.forename: Anca
authors.initials: A
authors.lastname: Dorhoi
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Ma
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Holmes
authors.forename: George
authors.initials: G
authors.lastname: Trendelenburg
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.forename: Stefan
authors.initials: S
authors.lastname: Bereswill
authors.forename: Mark
authors.initials: M
authors.lastname: van der Linden
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism* / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013301:Streptolysins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D013301:Streptolysins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C032290:plY protein, Streptococcus pneumoniae