Streptolysins are the primary inflammasome activators in macrophages during Streptococcus pyogenes infection. Issue 10 (18th September 2021)

• Record Type: Journal Article
• Authors: Richter, Johanna; Monteleone, Mercedes M; Cork, Amanda J; Barnett, Timothy C; Nizet, Victor; Brouwer, Stephan; Schroder, Kate; Walker, Mark J
• Is Part Of: Immunology and cell biology. Volume 99:Issue 10(2021)
• Page Start: 1040
• Page End: 1052
• Publication Date: 2021-09-18
• Subjects: IL‐1β -- inflammasome -- macrophages -- Streptococcus pyogenes -- streptolysin O -- streptolysin S; Immunology -- Periodicals; Cytology -- Periodicals; 616.079
• DOI: 10.1111/imcb.12499
• Languages: English
• ISSNs: 0818-9641

Abstract

Abstract: Group A Streptococcus (GAS) is a Gram‐positive bacterial pathogen that causes an array of infectious diseases in humans. Accumulating clinical evidence suggests that proinflammatory interleukin (IL)‐1β signaling plays an important role in GAS disease progression. The host regulates the production and secretion of IL‐1β via the cytosolic inflammasome pathway. Activation of the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome complex requires two signals: a priming signal that stimulates increased transcription of genes encoding the components of the inflammasome pathway, and an activating signal that induces assembly of the inflammasome complex. Here we show that GAS‐derived lipoteichoic acid can provide a priming signal for NLRP3 inflammasome activation. As only few GAS‐derived proteins have been associated with inflammasome‐dependent IL‐1β signaling, we investigated novel candidates that might play a role in activating the inflammasome pathway by infecting mouse bone marrow‐derived macrophages and human THP‐1 macrophage‐like cells with a panel of isogenic GAS mutant strains. We found that the cytolysins streptolysin O (SLO) and streptolysin S are the main drivers of IL‐1β release in proliferating logarithmic phase GAS. Using a mutant form of recombinant SLO, we confirmed that bacterial pore formation on host cell membranes is a key mechanism required for inflammasome activation. Our results suggest that streptolysins are major determinants of GAS‐induced inflammation and present an attractive target for therapeutic intervention. Abstract : Group A Streptococcus (GAS) interacts with the inflammasome pathway in host cells. Lipoteichoic acid derived from GAS can prime the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome for activation in mouse macrophages. Our study reveals that streptolysins are the main drivers of interleukin‐1β production in mouse and human macrophages during GAS infection, and that GAS strains of the serotypes emm1 and emm12 can induce robust inflammasome signaling that is strongly dependent on the production and pore‐forming ability of streptolysin O.