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Secreted Toxins and Extracellular Enzymes

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Kayan Tam1, Victor J. Torres2
  • Editors: Vincent A. Fischetti3, Richard P. Novick4, Joseph J. Ferretti5, Daniel A. Portnoy6, Miriam Braunstein7, Julian I. Rood8
    Affiliations: 1: Department of Microbiology, New York University School of Medicine, Alexandria Center for Life Science, New York, NY 10016; 2: Department of Microbiology, New York University School of Medicine, Alexandria Center for Life Science, New York, NY 10016; 3: The Rockefeller University, New York, NY; 4: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 5: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 6: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 7: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC; 8: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  • Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
  • Received 23 July 2018 Accepted 16 August 2018 Published 15 March 2019
  • Victor J. Torres, [email protected]
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  • Abstract:

    is a formidable pathogen capable of causing infections in different sites of the body in a variety of vertebrate animals, including humans and livestock. A major contribution to the success of as a pathogen is the plethora of virulence factors that manipulate the host’s innate and adaptive immune responses. Many of these immune modulating virulence factors are secreted toxins, cofactors for activating host zymogens, and exoenzymes. Secreted toxins such as pore-forming toxins and superantigens are highly inflammatory and can cause leukocyte cell death by cytolysis and clonal deletion, respectively. Coagulases and staphylokinases are cofactors that hijack the host’s coagulation system. Exoenzymes, including nucleases and proteases, cleave and inactivate various immune defense and surveillance molecules, such as complement factors, antimicrobial peptides, and surface receptors that are important for leukocyte chemotaxis. Additionally, some of these secreted toxins and exoenzymes can cause disruption of endothelial and epithelial barriers through cell lysis and cleavage of junction proteins. A unique feature when examining the repertoire of secreted virulence factors is the apparent functional redundancy exhibited by the majority of the toxins and exoenzymes. However, closer examination of each virulence factor revealed that each has unique properties that have important functional consequences. This chapter provides a brief overview of our current understanding of the major secreted virulence factors critical for pathogenesis.

  • Citation: Tam K, Torres V. 2019. Secreted Toxins and Extracellular Enzymes. Microbiol Spectrum 7(2):GPP3-0039-2018. doi:10.1128/microbiolspec.GPP3-0039-2018.


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is a formidable pathogen capable of causing infections in different sites of the body in a variety of vertebrate animals, including humans and livestock. A major contribution to the success of as a pathogen is the plethora of virulence factors that manipulate the host’s innate and adaptive immune responses. Many of these immune modulating virulence factors are secreted toxins, cofactors for activating host zymogens, and exoenzymes. Secreted toxins such as pore-forming toxins and superantigens are highly inflammatory and can cause leukocyte cell death by cytolysis and clonal deletion, respectively. Coagulases and staphylokinases are cofactors that hijack the host’s coagulation system. Exoenzymes, including nucleases and proteases, cleave and inactivate various immune defense and surveillance molecules, such as complement factors, antimicrobial peptides, and surface receptors that are important for leukocyte chemotaxis. Additionally, some of these secreted toxins and exoenzymes can cause disruption of endothelial and epithelial barriers through cell lysis and cleavage of junction proteins. A unique feature when examining the repertoire of secreted virulence factors is the apparent functional redundancy exhibited by the majority of the toxins and exoenzymes. However, closer examination of each virulence factor revealed that each has unique properties that have important functional consequences. This chapter provides a brief overview of our current understanding of the major secreted virulence factors critical for pathogenesis.

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Current models for PFT pore formation for (A) α-toxin and (B) the bicomponent PFTs. α-toxin is secreted as a monomer. Upon binding to the host receptor, ADAM-10, the toxin monomers oligomerize to form a heptameric prepore on the target cell surface. The prestem domains of the prepore then extend to form a β-barrel pore that punctures the target cell membrane. The bicomponent PFTs are also secreted as monomers (except LukAB, which is secreted as dimers). The S-subunit recognizes the target cell by binding to cell surface receptors (LukPQ is an exception; the F-subunit LukQ is the receptor recognition subunit). These receptors are typically G-protein-coupled receptors (except for LukAB, which binds to the integrin CD11b). Upon receptor binding, the S-subunit dimerizes with the F-subunit, followed by oligomerization of three additional leukocidin dimers, resulting in an octameric prepore. Similar to the α-toxin pore formation model, the prestem domains of the prepore extend to form a β-barrel pore, thus disrupting the target cell membrane.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Structures of (A to C) α-toxin and (D to G) the bicomponent PFT, HlgAB. The α-toxin monomer (PDB:4U6V) ( 351 ). The amino latch is colored blue, the cap domain red, the rim domain pink, and the prestem domain green. The α-toxin heptamer (7AHL) ( 4 ). Each α-toxin is colored a different shade of pink to denote individual protomers. The amino latches are highlighted in blue, and the β-barrel pore is green. The monomers of HlgA (2QK7) ( 352 ) and HlgB (1LKF) ( 353 ). The amino latch of HlgB is blue; the cap domain for HlgA is cyan and HlgB is beige; the rim domains are yellow for HlgA and pink for HlgB; and the prestem domains are green. The HlgAB octamer (3B07) ( 33 ). The HlgA protomers are cyan, the HlgB protomers are beige, and the β-barrel pore is green.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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PFTs and their receptor, species, and cell type specificities. Currently, is known to produce eight β-barrel PFTs. Each of these PFTs targets different cell surface receptors. While some PFTs share the same receptors, they can differ in their species specificity. Collectively, the PFTs exert their sublytic and lytic effects on a variety of cells, including erythrocytes, endothelial cells, epithelial cells, neutrophils, monocytes, macrophages, dendritic cells, and T cells.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Phylogenic tree of PFTs. The tree is constructed based on the mature protein sequences using the DNASTAR MegAlign ClustalW method for multiple sequence alignment.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Phylogenic tree of SAgs. The tree is constructed based on the mature protein sequences using the DNASTAR MegAlign ClustalW method for multiple sequence alignment.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Crystal structures of superantigens in complex with their cellular targets. The T cell superantigen, SEB, in complex with the TCR and MHC II molecule (4C56) ( 116 ). SEB (blue) cross-links the α-chain of MHC (dark green) to the Vβ TCR (orange) to induce T cell proliferation that results in T cell anergy and/or apoptosis. The B cell superantigen, SpA (teal), in complex with the Fab fragment (pink/magenta) (1DEE) ( 138 ). Conventional antigens bind to B cell receptors at the complementarity-determining region (blue), a hypervariable region that confers antigen specificities. SpA binds at a constant region of the receptor to activate B cells for supraclonal expansion, which leads to clonal deletion of SpA-activated B cells.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Overlay of the crystal structures of ETA and ETB. ETA (1EXF, green) ( 174 ) and ETB (1QTF, blue) ( 173 ) share high structural identity. ETs cause SSSS by cleaving Dsg1 at the epithelial cell junctions. Both ETs are serine proteases. Loop D and the catalytic triad are highlighted in pink for ETA and red for ETB.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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produces cofactors that hijack the host’s coagulation system. Coa and vWbp bind to prothrombin and alter the conformation of the protein to form the complex, staphylothrombin. This complex is highly active and cleaves fibrinogens to fibrins, promoting the formation of fibrinous clots. Sak binds to plasmin to form the Sak-plasmin complex. Sak stabilizes plasmin to enhance enzymatic activity. Sak-plasmin cleaves plasminogen to form plasmin, which breaks down fibrin clots.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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The crystal structure of Sak in complex with two plasminogen molecules (1BUI) ( 215 ). While Sak binding to plasminogen does not have enzymatic activity, the trimeric complex captures how Sak may bind to plasmin to cleave plasminogen. Sak (orange) is in complex with plasminogen (blue), exposing the catalytic site (red). Sak facilitates the docking of the substrate plasminogen (pink) to promote cleavage by plasmin.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Staphylococcal protease cascade. The metalloprotease, Aur, is activated by autoproteolysis after protein secretion. Aur is required to activate the serine protease, SspA. SspA processes one of the staphopains, SspB, from zymogen to active enzyme. The other staphopain, ScpA, is activated by autoproteolysis. Both staphopains are inhibited by staphostatins prior to secretion. SspB is inhibited by SspC, and ScpA is inhibited by ScpB.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Staphopain-staphostatin complex (1PXV) ( 293 ). Staphopain SspB (blue) has two domains: the L-domain is helical, and the R-domain consists of β-strands that fold into a β-barrel-like structure. The catalytic site of SspB is highlighted in red. Staphopain SspC (beige) is a single domain protein composed of eight β-strands forming a single mixed β-barrel domain. SspC is a competitive inhibitor of SspB, directly blocking substrate access to the active site.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Phylogenic tree of Spls. The tree is constructed based on the mature protein sequences using the DNASTAR MegAlign ClustalW method for multiple sequence alignment. Crystal structure of SplA (2W7S) ( 299 ). SplA has two domains connected by a linker (cyan). Domain 1 (light purple) consists of α-helices and β-strands, and domain 2 (blue) consists of of β-strands. Both domains fold into a β-barrel structure. The catalytic triad (red) is located at the center between the two domains.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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secretes many different toxins and enzymes. Superantigens are proteins that have high mitogenic properties, causing T and B cell expansions that result in clonal deletion and massive cytokine production. Cytotoxins, such as α-toxin and the leukocidins, cause cytokine production, hemolysis, and leukocyte cell death through targeting specific cell surface receptors. The amphiphilic PSM peptides mediate cytolysis by inserting into the lipid bilayer of cell membranes. Enzymes, such as β-toxin and the ETs, cause cytotoxicity on mammalian cells, resulting in cell death, inflammation, and tissue barrier disruptions. Other enzymes, including various proteases and nucleases, mediate host protein degradations, thwarting many important host immune surveillance and defense molecules. These enzymes can also act on self-proteins to degrade biofilms for bacterial dissemination. Lipases and FAME work synergistically to degrade lipids in the environment for nutrients. Cofactors, including Coa, vWbp, and Sak, bind and activate host zymogens in the coagulation system to mediate clot formation and dissolution. Altogether, these toxins and enzymes provide critical nutrients (i.e., iron and carbon) that are important for the growth and survival of the bacteria. Importantly, they target various aspects of host immune defenses, thus contributing to the overall virulence of during infections.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Major exotoxins produced by

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Major secreted cofactors and enzymes produced by

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018
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Consensus cleavage sequence of Spls

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0039-2018

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