ADAM10 Mediates Vascular Injury Induced by Staphylococcus aureus α-Hemolysin

Powers, Michael E.; Kim, Hwan Keun; Wang, Yan; Wardenburg, Juliane Bubeck

doi:10.1093/infdis/jis192

Cited by 161 publications

(179 citation statements)

References 17 publications

(28 reference statements)

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“…Consistent with this, bronchoalveolar lavage after in vivo infection with wild-type S. aureus showed a release of N-terminal fragments of E-cadherin, whereas an alpha-toxin-deficient mutant did not have this effect (436). When mice were treated with a metalloprotease inhibitor, they survived an otherwise lethal S. aureus lung infection and showed increased resistance to an intravenous challenge (436,437). Thus, alpha-toxin causes barrier dysfunction through hijacking of a host molecular pathway.…”

Section: Hijacking Of Host Factorsmentioning

confidence: 74%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

344

351

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SUMMARY Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae , group A and B streptococci, Staphylococcus aureus , Escherichia coli , and Mycobacterium tuberculosis . PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo . This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

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Section: Hijacking Of Host Factorsmentioning

confidence: 74%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

344

351

View full text Add to dashboard Cite

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“…Hyperproduction of alpha-toxin is associated with enhanced virulence in strains of both epidemic (USA300 and USA500) and endemic (ST93) community-associated methicillin-resistant S. aureus (CA-MRSA) isolates (20,21). Studies with a number of animal models have also suggested that alpha-toxin is a key virulence factor in the pathogenesis of S. aureus infections, including pneumonia (22)(23)(24)(25), skin and soft tissue infections (26,27), and bloodstream infections (28).…”

mentioning

confidence: 99%

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Sharma-Kuinkel

Wu²,

Tabor³

et al. 2015

J Clin Microbiol

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c Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 g/ml, versus failure, 1.09 g/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study. Staphylococcus aureus is a leading cause of bacterial infections (1-4), including skin and soft tissue infections (5), pneumonia (6), bacteremia (7), endocarditis (8-10), and bone and joint infections (11). The risk of invasive S. aureus infections is significantly higher among certain subgroups, including hemodialysisdependent patients and postoperative patients (12-14).These high-risk subpopulations are potential candidates for novel forms of prevention or treatment against invasive S. aureus infections.Alpha-toxin, a ␤-barrel pore-forming exotoxin encoded by hla (15, 16), is a key virulence factor produced by most S. aureus isolates (17, 18). It binds to ADAM10 (the A disintegrin and metalloproteinase domain-containing protein 10) on target cell membranes and then heptamerizes to generate a transmembrane pore, resulting in cell lysis (19). Hyperproduction of alpha-toxin is associated with enhanced virulence in strains of both epidemic (USA300 and USA500) and endemic (ST93) community-associated methicillin-resistant S. aureus (CA-MRSA) isolates (20,21). Studies with a number of animal models have also suggested that al...

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“…Hla is a pore-forming cytotoxin that has been extensively studied for its contribution to the pathogenesis of pneumonia, skin and soft tissue infection, sepsis, endocarditis, corneal infections, central nervous system infection, and mastitis (13)(14)(15)(16)(17)(18)(19)(20)(21). Binding of Hla to its receptor ADAM10 (a disintegrin and metalloprotease 10) on target host cells facilitates pore formation, cellular membrane injury, and damage to the tissue barrier function (16,(22)(23)(24). At high toxin concentrations on susceptible cells, lytic injury predominates, while subcytolytic concentrations of Hla promote the rapid upregulation of the metalloprotease activity of ADAM10 in a toxin pore-dependent manner (16,(22)(23)(24).…”

mentioning

confidence: 99%

“…Binding of Hla to its receptor ADAM10 (a disintegrin and metalloprotease 10) on target host cells facilitates pore formation, cellular membrane injury, and damage to the tissue barrier function (16,(22)(23)(24). At high toxin concentrations on susceptible cells, lytic injury predominates, while subcytolytic concentrations of Hla promote the rapid upregulation of the metalloprotease activity of ADAM10 in a toxin pore-dependent manner (16,(22)(23)(24). ADAM10 activation in turn promotes the untimely, pathological cleavage of native ADAM10 substrates such as E-cadherin and VE-cadherin, causing injury to the barrier functions of the pulmonary epithelium, the epidermis, and the vascular endothelium (16,23,24).…”

mentioning

confidence: 99%

The psm α Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection

et al. 2014

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Staphylococcus aureus is a leading cause of human bacterial infection, causing a wide spectrum of disease ranging from skin and soft tissue infections to life-threatening pneumonia and sepsis. S. aureus toxins play an essential role in disease pathogenesis, contributing to both immunomodulation and host tissue injury. Prominent among these toxins are the membrane-active poreforming cytolysin alpha-toxin (Hla) and the amphipathic ␣-helical phenol-soluble modulin (PSM) peptides. As deletion of either the hla or psm locus leads to a phenotypically similar virulence defect in skin and soft tissue infection, we sought to determine the relative contribution of each locus to disease pathogenesis. Here we show that production of Hla can be modulated by PSM expression. An S. aureus mutant lacking PSM expression exhibits a transcriptional delay in hla mRNA production and therefore fails to secrete normal levels of Hla at early phases of growth. This leads to attenuation of virulence in vitro and in murine skin and lung models of infection, correlating with reduced recovery of Hla from host tissues. Production of Hla and restoration of staphylococcal virulence can be achieved in the psm mutant by plasmid-driven overexpression of hla. Our study suggests the coordinated action of Hla and PSMs in host tissue during early pathogenesis, confirming a major role for Hla in epithelial injury during S. aureus infection. These findings highlight the possibility that therapeutics targeting PSM production may simultaneously prevent Hla-mediated tissue injury.

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ADAM10 Mediates Vascular Injury Induced by Staphylococcus aureus α-Hemolysin

Cited by 161 publications

References 17 publications

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

The psm α Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection

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