Activation of the NLRP3 Inflammasome by Group B Streptococci

Abstract

Group B streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show here that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1β and Il-18. IL-1β release required both pro-IL-1β transcription and caspase-1-dependent proteolytic cleavage of intracellular pro-IL-1β. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro-IL-1β mRNA in response to GBS. Pro-IL-1β cleavage and secretion of the mature IL-1β form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis-associated speck-like protein containing a CARD (ASC) adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of β-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, ASC or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome.

RNA and β-Hemolysin of Group B Streptococcus Induce Interleukin-1β (IL-1β) by Activating NLRP3 Inflammasomes in Mouse Macrophages

“…We also showed that GBS induces IL-1␤ production in an NLRP3-dependent manner in dendritic cells (13). In this study, we demonstrate that GBS activates the NLRP3 inflammasome by a mechanism that requires hemolysin-mediated lysosomal leakage.…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…[40][41][42] Viral nucleic acids are usually detected by the retinoic acidinducible gene 1 and AIM2-like receptor (ALR) inflammasomes; however, several viruses and their components, including influenza virus (the proton-selective ion channel protein M2), 43 encephalomyocarditis virus (viroporin 2B), 44 poliovirus and enterovirus 71 (non-structural 2B protein), 44 rhinovirus (2B proteins), 45 human respiratory syncytial virus (small hydrophobic protein), 46 are sufficient to stimulate NLRP inflammasome activation. Recent studies have revealed a crucial protective role of inflammasome activation during viral infection, via an increase in adaptive immune activation with limited tissue damage.…”

IL-1 signaling inhibits Trichophyton rubrum conidia development and modulates the IL-17 response in vivo

“…6 NLRP3 inflammasome is activated by a diverse set of stimuli, but, classically, it is associated to the sensing of noxious agents as monosodium urate crystals (associated to gout) and extracellular ATP, particles as silica and asbestos, and also pathogens. 7 Among infectious agents, bacteria, as Streptococcus agalactiae 8 ; viruses, as Rift Valley fever virus 9 ; protozoans, as Plasmodium berghei 10 and fungi, as Candida albicans 11 were shown to activate this system. This multitude of potential activators places NLRP3 as a prominent actor in many diseases associated to inflammatory conditions.…”