Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2022

Streptolysins are the primary inflammasome activators in macrophages during Streptococcus pyogenes infection (82624)

Johanna Richter 1 , Mercedes M Monteleone 2 , Amanda J Cork 1 , Tim C Barnett 1 3 , Victor Nizet 4 , Stephan Brouwer 1 , Kate Schroder 2 , Mark J Walker 1
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
  2. Australian Infectious Diseases Research Centre and Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  3. Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
  4. Department of Pediatrics, University of California at San Diego School of Medicine, La Jolla, California, USA

Introduction

Group A Streptococcus (GAS) is a Gram-positive bacterial pathogen that causes an array of infectious diseases in humans1. Accumulating clinical evidence suggests that pro-inflammatory interleukin-1β (IL-1β) signalling plays an important role in GAS disease progression2. The host regulates the production and secretion of IL-1β via the cytosolic inflammasome pathway3. Activation of the NLRP3 inflammasome 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. Only few GAS-derived proteins have been associated with NLRP3-dependent IL-1β release4-6. Here we investigated novel candidates that might play a role in inflammasome signalling in macrophages7.

Methods

As macrophages are an important source of IL-1β production during GAS infection8, we infected mouse bone marrow-derived macrophages and human THP‐1 macrophage-like cells with a panel of isogenic GAS mutant strains containing mutations of GAS virulence genes and compared their ability to trigger inflammasome signalling to that of the invasive wildtype strain.

Results

IL-1β secretion triggered by GAS was significantly reduced in the absence of the cytolysins streptolysin O and streptolysin S. A mutant form of recombinant streptolysin O that is incapable of forming pores in host cell membranes failed to induce IL-1β secretion.

Conclusion

Our results suggest that streptolysins are the main drivers of IL‐1β release during GAS infection and present an attractive target for therapeutic intervention. We confirmed that membrane pore formation in host cells is a key mechanism required for inflammasome signalling triggered by GAS.

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