Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los, Ferdinand C. O.; Randis, Tara M.; Aroian, Raffi V.; Ratner, Adam J.

doi:10.1128/mmbr.00052-12

Cited by 350 publications

(361 citation statements)

References 485 publications

(372 reference statements)

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“…S. pneumoniae and S. aureus can secrete pore-forming toxins during infection that aid in bacterial invasion. PFTs are the largest single class of proteinaceous bacterial toxins (19,20), and many PFTs gain access to the host cell through binding to cholesterol or lipid derivatives in lipid rafts on the cell surface, resulting in subsequent oligomerization and pore formation (21,22). Pneumolysin (PLY), a member of the cholesteroldependent cytolysin family, is a major virulence factor that is expressed by virtually all clinical isolates of S. pneumoniae.…”

mentioning

confidence: 99%

Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells

Statt

Ruan

Hung

et al. 2015

Am J Respir Cell Mol Biol

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Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10-1,000 nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, a-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin associated bacterial infections.Keywords: airway epithelium; pneumolysin; simvastatin; cholesterol; pneumonia Clinical RelevanceOur study dissects the cellular and molecular protection mechanisms of statins in an isolated airway epithelial cell-bacterial pore-forming toxin context. This research can fill large gaps in our understanding of how statins contribute to the reduced pathology observed during pneumonia and other bacterial infections. The better understanding of the molecular mechanisms in the statin-mediated protection will further affect the therapeutic development of host-centric approach therapies in combating microbial infections.

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mentioning

confidence: 99%

Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells

Statt

Ruan

Hung

et al. 2015

Am J Respir Cell Mol Biol

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“…For the purpose of invasion, several pathogenic bacteria produce PFTs, such as β-barrel-type aerolysins, which can oligomerize and form pores in host-cell membranes (12,13). The aerolysin domain is defined according to its structural similarity to the transmembrane domain of aerolysin toxins.…”

mentioning

confidence: 99%

Host-derived, pore-forming toxin–like protein and trefoil factor complex protects the host against microbial infection

Xiang

Yan

Guo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

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Aerolysins are virulence factors belonging to the bacterial β-poreforming toxin superfamily. Surprisingly, numerous aerolysin-like proteins exist in vertebrates, but their biological functions are unknown. βγ-CAT, a complex of an aerolysin-like protein subunit (two βγ-crystallin domains followed by an aerolysin pore-forming domain) and two trefoil factor subunits, has been identified in frogs (Bombina maxima) skin secretions. Here, we report the rich expression of this protein, in the frog blood and immune-related tissues, and the induction of its presence in peritoneal lavage by bacterial challenge. This phenomena raises the possibility of its involvement in antimicrobial infection. When βγ-CAT was administrated in a peritoneal infection model, it greatly accelerated bacterial clearance and increased the survival rate of both frogs and mice. Meanwhile, accelerated Interleukin-1β release and enhanced local leukocyte recruitments were determined, which may partially explain the robust and effective antimicrobial responses observed. The release of interleukin-1β was potently triggered by βγ-CAT from the frog peritoneal cells and murine macrophages in vitro. βγ-CAT was rapidly endocytosed and translocated to lysosomes, where it formed high molecular mass SDS-stable oligomers (>170 kDa). Lysosomal destabilization and cathepsin B release were detected, which may explain the activation of caspase-1 inflammasome and subsequent interleukin-1β maturation and release. To our knowledge, these results provide the first functional evidence of the ability of a host-derived aerolysin-like protein to counter microbial infection by eliciting rapid and effective host innate immune responses. The findings will also largely help to elucidate the possible involvement and action mechanisms of aerolysin-like proteins and/or trefoil factors widely existing in vertebrates in the host defense against pathogens.innate immunity | infectious disease | interleukin-1beta

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“…PFTs were used as live vaccines in various disease models, but successful immunization against a PFT does not always prevent disease (46). Other examples such as inhibiting PFTs and using competitive inhibitors were shown to prevent or cure the infection (46).…”

Section: Discussionmentioning

confidence: 99%

“…For the treatment of increasingly antibiotic-resistant bacteria, the development of new, narrower-spectrum or virulence-targeted antimicrobial therapeutics is necessary (45,46). PFTs were used as live vaccines in various disease models, but successful immunization against a PFT does not always prevent disease (46).…”

Section: Discussionmentioning

confidence: 99%

PSM Peptides of Staphylococcus aureus Activate the p38–CREB Pathway in Dendritic Cells, Thereby Modulating Cytokine Production and T Cell Priming

Armbruster

Richardson

Schreiner

et al. 2016

The Journal of Immunology

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The challenging human pathogen Staphylococcus aureus has highly efficient immune evasion strategies for causing a wide range of diseases, from skin and soft tissue to life-threatening infections. Phenol-soluble modulin (PSM) peptides are major pathogenicity factors of community-associated methicillin-resistant S. aureus strains. In previous work, we demonstrated that PSMs in combination with TLR2 ligand from S. aureus induce tolerogenic dendritic cells (DCs) characterized by the production of high amounts of IL-10, but no proinflammatory cytokines. This in turn promotes the activation of regulatory T cells while impairing Th1 response; however, the signaling pathways modulated by PSMs remain elusive. In this study, we analyzed the effects of PSMs on signaling pathway modulation downstream of TLR2. TLR2 stimulation in combination with PSMα3 led to increased and prolonged phosphorylation of NF-κB, ERK, p38, and CREB in mouse bone marrow–derived DCs compared with single TLR2 activation. Furthermore, inhibition of p38 and downstream MSK1 prevented IL-10 production, which in turn reduced the capacity of DCs to activate regulatory T cells. Interestingly, the modulation of the signaling pathways by PSMs was independent of the known receptor for PSMs, as shown by experiments with DCs lacking the formyl peptide receptor 2. Instead, PSMs penetrate the cell membrane most likely by transient pore formation. Moreover, colocalization of PSMs and p38 was observed near the plasma membrane in the cytosol, indicating a direct interaction. Thus, PSMs from S. aureus directly modulate the signaling pathway p38–CREB in DCs, thereby impairing cytokine production and in consequence T cell priming to increase the tolerance toward the pathogen.

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Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Cited by 350 publications

References 485 publications

Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells

Statin-Conferred Enhanced Cellular Resistance against Bacterial Pore-Forming Toxins in Airway Epithelial Cells

Host-derived, pore-forming toxin–like protein and trefoil factor complex protects the host against microbial infection

PSM Peptides of Staphylococcus aureus Activate the p38–CREB Pathway in Dendritic Cells, Thereby Modulating Cytokine Production and T Cell Priming

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