Group A streptococcal M protein activates the NLRP3 inflammasome

Valderrama, J. Andrés; Riestra, Angelica M.; Gao, Nana; LaRock, Christopher N.; Gupta, Naveen; Ali, Shariq; Hoffman, Hal M.; Ghosh, Partho; Nizet, Victor

doi:10.1038/s41564-017-0005-6

Cited by 74 publications

(88 citation statements)

References 47 publications

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“…To our knowledge, this is the first report that M1 protein can induce platelet apoptosis. M1 protein has, however, recently been reported to induce programmed cell death, pyroptosis, in macrophages (39).…”

Section: Discussionmentioning

confidence: 99%

Complement Activation Occurs at the Surface of Platelets Activated by Streptococcal M1 Protein and This Results in Phagocytosis of Platelets

Palm

Sjöholm

Malmström

et al. 2019

The Journal of Immunology

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Platelets circulate the bloodstream and principally maintain hemostasis. Disturbed hemostasis, a dysregulated inflammatory state, and a decreased platelet count are all hallmarks of severe invasive Streptococcus pyogenes infection, sepsis. We have previously demonstrated that the released M1 protein from S. pyogenes activates platelets, and this activation is dependent on the binding of M1 protein, fibrinogen, and M1-specific IgG to platelets in susceptible donors. In this study, we characterize the M1-associated protein interactions in human plasma and investigate the acquisition of proteins to the surface of activated platelets and the consequences for platelet immune function. Using quantitative mass spectrometry, M1 protein was determined to form a protein complex in plasma with statistically significant enrichment of fibrinogen, IgG3, and complement components, especially C1q. Using flow cytometry, these plasma proteins were also confirmed to be acquired to the platelet surface, resulting in complement activation on M1-activated human platelets. Furthermore, we demonstrated an increased phagocytosis of M1-activated platelets by monocytes, which was not observed with other physiological platelet agonists. This reveals a novel mechanism of complement activation during streptococcal sepsis, which contributes to the platelet consumption that occurs in sepsis.

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Section: Discussionmentioning

confidence: 99%

Complement Activation Occurs at the Surface of Platelets Activated by Streptococcal M1 Protein and This Results in Phagocytosis of Platelets

Palm

Sjöholm

Malmström

et al. 2019

The Journal of Immunology

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“…Mechanistically, cell wall fragments increase lysosomal permeability and thereby facilitate release of cathepsin B into the cytoplasm to activate NLRP3 (120). The cell surface protein M1 of Streptococcus pyogenes can likewise activate the NLRP3 inflammasome upon clathrin-mediated endocytosis, in a manner dependent on potassium efflux (121). A further study suggests that the muramyl dipeptide of Bacillus anthracis is detected by its cognate cytosolic sensor, NOD2, which has been reported to recruit NLRP1 to mediate caspase-1 activation and secretion of IL-1␤ (122).…”

Section: Other Cell Wall Componentsmentioning

confidence: 99%

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

Hayward

Mathur

Ngo

et al. 2018

Microbiol Mol Biol Rev

130

111

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Infection is a dynamic biological process underpinned by a complex interplay between the pathogen and the host. Microbes from all domains of life, including bacteria, viruses, fungi, and protozoan parasites, have the capacity to cause infection. Infection is sensed by the host, which often leads to activation of the inflammasome, a cytosolic macromolecular signaling platform that mediates the release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and cleavage of the pore-forming protein gasdermin D, leading to pyroptosis. Host-mediated sensing of the infection occurs when pathogens inject or carry pathogen-associated molecular patterns (PAMPs) into the cytoplasm or induce damage that causes cytosolic liberation of danger-associated molecular patterns (DAMPs) in the host cell. Recognition of PAMPs and DAMPs by inflammasome sensors, including NLRP1, NLRP3, NLRC4, NAIP, AIM2, and Pyrin, initiates a cascade of events that culminate in inflammation and cell death. However, pathogens can deploy virulence factors capable of minimizing or evading host detection. This review presents a comprehensive overview of the mechanisms of microbe-induced activation of the inflammasome and the functional consequences of inflammasome activation in infectious diseases. We also explore the microbial strategies used in the evasion of inflammasome sensing at the host-microbe interaction interface.

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“…However, after GAS infection in our setup the IL-1β mRNA regulation varied from subject to subject. The slight increase in IL-1β observed at the protein level for some subjects may result from an inflammasome activation (58). A single-nucleotide polymorphism in the enhancerpromoter region of IL1B gene has been associated with puerperal GAS sepsis susceptibility and could be responsible for the differences we observed (59).…”

Section: Discussionmentioning

confidence: 63%

Streptococcus pyogenes infects human endometrium by limiting its immune response

Weckel¹,

Guilbert²,

Lambert³

et al. 2019

Preprint

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Group A Streptococcus (GAS), a Gram-positive human-specific pathogen yields 517,000 deaths annually worldwide, including 163,000 due to invasive infections and among them puerperal fever. GAS is their most feared etiologic agent. Puerperal fever still accounts for more than 75,000 maternal deaths annually and before the introduction of efficient prophylactic measures 10% childbirths were followed by the mother's death. Yet little is known regarding GAS invasive infection establishment or GAS efficiency in causing postpartum infection. To characterize its early steps, we set up coordinated analyses of ex vivo infection of the human decidua, the puerperal fever portal of entry. We analyzed GAS behavior and the immune response triggered. We demonstrate that GAS (i) benefits from tissue secreted products to multiply; (ii) invades the tissue and leads to the death of half the cells within two hours via SpeB protease and Streptolysin O activities, respectively; (iii) impairs the tissue immune response. Immune impairment occurs both at the RNA level, with the induction of only a restricted immediate innate immune response, and at the protein level, in a SLO-and SpeB-dependent manner. Our study indicates that GAS efficient decidua invasion and immune response restraint favor its propensity to develop rapid invasive infections in a gynecological-obstetrical context.

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Group A streptococcal M protein activates the NLRP3 inflammasome

Cited by 74 publications

References 47 publications

Complement Activation Occurs at the Surface of Platelets Activated by Streptococcal M1 Protein and This Results in Phagocytosis of Platelets

Complement Activation Occurs at the Surface of Platelets Activated by Streptococcal M1 Protein and This Results in Phagocytosis of Platelets

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

Streptococcus pyogenes infects human endometrium by limiting its immune response

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