Streptococcal<i>sagA</i>activates a proinflammatory response in mast cells by a sublytic mechanism

Beek, Christopher von; Waern, Ida; Eriksson, Jens; Melo, Fabio Rabelo; Robinson, Carl; Waller, Andrew S.; Sellin, Mikael E.; Guss, Bengt; Pejler, Gunnar

doi:10.1111/cmi.13064

Cited by 9 publications

(23 citation statements)

References 52 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The contribution of SLS to the pathogenesis of streptococcal necrotizing soft tissue infection by S. pyogenes and Group G streptococci was also reported 133 . Moreover, the p38 and Erk1/2 signaling pathways induced by SLS were found to play a central role in the proinflammatory response of mast cells against S. equi 134 …”

Section: Slsmentioning

confidence: 87%

Diversity of β‐hemolysins produced by the human opportunistic streptococci

Tabata

Nagamune

2021

Microbiology and Immunology

View full text Add to dashboard Cite

The genus Streptococcus infects a broad range of hosts, including humans. Some species, such as S. pyogenes, S. agalactiae, S. pneumoniae, and S. mutans, are recognized as the major human pathogens, and their pathogenicity toward humans has been investigated. However, many of other streptococcal species have been recognized as opportunistic pathogens in humans, and their clinical importance has been underestimated. In our previous study, the Anginosus group streptococci (AGS) and Mitis group streptococci (MGS) showed clear β‐hemolysis on blood agar, and the factors responsible for the hemolysis were homologs of two types of β‐hemolysins, cholesterol‐dependent cytolysin (CDC) and streptolysin S (SLS). In contrast to the regular β‐hemolysins produced by streptococci (typical CDCs and SLSs), genetically, structurally, and functionally atypical β‐hemolysins have been observed in AGS and MGS. These atypical β‐hemolysins are thought to affect and contribute to the pathogenic potential of opportunistic streptococci mainly inhabiting the human oral cavity. In this review, we introduce the diverse characteristics of β‐hemolysin produced by opportunistic streptococci, focusing on the species/strains belonging to AGS and MGS, and discuss their pathogenic potential.

show abstract

Section: Slsmentioning

confidence: 87%

Diversity of β‐hemolysins produced by the human opportunistic streptococci

Tabata

Nagamune

2021

Microbiology and Immunology

View full text Add to dashboard Cite

show abstract

“…Bacterial recognition by MCs has often been accredited to TLRs 6,9 . However, work by us and others have in addition shown that sublytic levels of bacterial pore-forming toxins can elicit secretion of cytokines, including IL-6, from MCs [14][15][16] . We therefore asked if MC activation by S.Tm could be ascribed to i) classical recognition of bacterial PAMPs, ii) membrane-perturbing effects of the TTSS-1 translocon (in analogy to pore-forming toxins), or iii) alternative mechanism(s).…”

Section: Mast Cells and Salmonella Coexist In The Infected Murine Gutmentioning

confidence: 94%

A Two-Step Activation Mechanism Enables Mast Cells to Differentiate their Response between Extracellular and Invasive Enterobacterial Infection

von Beek,

Fahlgren,

Geiser

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Mast cells (MCs) localize to mucosal tissues and contribute to innate immune defenses against infection. How MCs sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other closely related enterobacteria, we here demonstrate that MCs can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and MCs colocalize in the Salmonella-infected mouse gut. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure LPS, causes a slow and modest induction of MC cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human MCs triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to promote the full-blown MC response. Supernatants from S.Tm-infected MCs boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that MCs can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.

show abstract

“…Based on these data, the authors concluded that bacteria-derived SLS at sublytic concentrations is a major stimulus for mast cell activation leading to proinflammatory gene expression and cytokine production. It should be noted, however, that in contrast to CDCs, SLS induced only week degranulation (106). Kramer et al (111) examined the effect of a-hemolysin, a protein toxin that assembles on membranes to form a heptameric pore structure (133).…”

Section: Comparable Response Of Mast Cells To Cdcs and Other Pore-forming Compoundsmentioning

confidence: 99%

“…A recent study showed that BMMCs responded vividly to wild-type S. equi by upregulating a panel of proinflammatory genes and secreting proinflammatory IL-6, TNF-α, and monocyte chemoattractant protein (MCP)1 ( 106 ). However, this response was abrogated entirely in S. equi lacking the sagA gene encoding SLS.…”

Section: Comparable Response Of Mast Cells To Cdcs and Other Pore-forming Compoundsmentioning

confidence: 99%

“…During their experiments focused on S. equi interaction with mast cells, von Beek et al. ( 106 ) used another pore-forming compound, saponin, and a steroid glycoside detergent digitonin to determine whether SLS and saponins trigger BMMCs in a similar way. They found that saponin, which forms tiny pores in the plasma membrane ( 134 , 135 ) at sublytic concentrations, triggered IL-6 and TNF production similarly to SLS.…”

Section: Comparable Response Of Mast Cells To Cdcs and Other Pore-forming Compoundsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

2021

View full text Add to dashboard Cite

Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

show abstract

StreptococcalsagAactivates a proinflammatory response in mast cells by a sublytic mechanism

Cited by 9 publications

References 52 publications

Diversity of β‐hemolysins produced by the human opportunistic streptococci

Diversity of β‐hemolysins produced by the human opportunistic streptococci

A Two-Step Activation Mechanism Enables Mast Cells to Differentiate their Response between Extracellular and Invasive Enterobacterial Infection

Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

Contact Info

Product

Resources

About