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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Streptococcus pyogenes induces oncosis in macrophages through the activation of an inflammatory programmed cell death
Oliver Goldmann1, Inka Sastalla, Melissa Wos-Oxley
1Infection Immunology Research Group, Department of Microbial Pathogenesis, HZI-Helmholtz Centre for Infection Research, Braunschweig, Germany.
Abstract:
Macrophages are crucial components of the host defence against Streptococcus pyogenes. Here, we demonstrate the ability of S. pyogenes to kill macrophages through the activation of an inflammatory programmed cell death pathway. Macrophages exposed to S. pyogenes exhibited extensive cytoplasmic vacuolization, cellular and organelle swelling and rupture of the plasma membrane typical of oncosis. The cytotoxic effect of S. pyogenes on macrophages is mediated by the streptococcal cytolysins streptolysin S and streptolysin O and does not require bacterial internalization. S. pyogenes-induced death of macrophages was not affected by the addition of osmoprotectant, implicating the activation of an orchestrated cell death pathway rather than a simple osmotic lysis. This programme cell death pathway involves the loss of mitochondria transmembrane potential (Deltapsi(m)) and was inhibited by the addition of exogenous glycine, which has been shown to prevent necrotic cell death by blocking the opening of death channels in the plasma membrane. The production of reactive oxygen species and activation of calpains were identified as mediators of the cell death process. We conclude that activation of the inflammatory programmed cell death pathway in macrophages could constitute an important pathogenic mechanism by which S. pyogenes evades host immune defences and causes disease.
Insights
Streptococcus pyogenes kills macrophages via an inflammatory programmed cell death pathway, not simple lysis. This mechanism, involving specific toxins, helps the bacteria evade immune defenses during infection.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Macrophages are key immune cells for combating Streptococcus pyogenes infections.
- Understanding how S. pyogenes interacts with and overcomes host defenses is crucial for disease control.
Purpose of the Study:
- To investigate the mechanism by which Streptococcus pyogenes induces macrophage death.
- To identify the specific bacterial factors and cellular pathways involved in this process.
Main Methods:
- Exposure of macrophages to S. pyogenes and analysis of cell death morphology (oncosis).
- Assessment of the role of streptococcal cytolysins (streptolysin S and O) and bacterial internalization.
- Investigation of cell death pathway involvement using osmoprotectants, glycine, reactive oxygen species, and calpain activity.
Main Results:
- S. pyogenes induces macrophage death characterized by oncosis, involving cytoplasmic vacuolization and membrane rupture.
- Bacterial cytolysins streptolysin S and O mediate this cytotoxic effect, independent of bacterial entry.
- The cell death pathway involves loss of mitochondrial membrane potential and is inhibited by glycine, indicating programmed cell death.
Conclusions:
- Streptococcus pyogenes activates an inflammatory programmed cell death pathway in macrophages.
- This programmed cell death is mediated by reactive oxygen species and calpain activation.
- This mechanism is a key virulence factor allowing S. pyogenes to evade host immune responses and cause disease.
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