Chapter 38 : Exotoxins

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Exotoxins, Page 1 of 2

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This chapter talks about exotoxins fall into three general groups: (i) membrane-active agents, (ii) pyrogenic toxin superantigens (PTSAgs), and (iii) exfoliative toxins (ETs). Researchers proposed the existence of delta-toxin as the fourth cytolytic toxin in 1947. Panton-Valentine leukocidin (PVL) and gamma-toxin are two prototypic bicomponent toxins. Unfortunately, the rapid rate of new toxin discovery has resulted in more than one SE being given the same designation in the literature. Therefore, it is now recommended that nomenclature for new PTSAgs be assigned by the International Nomenclature Committee for Staphylococcal Superantigens prior to publication. The major cytokines induced initially include IL-1, tumor necrosis factors alpha and beta, interferon-γ, and IL-2. The ETs have been conclusively implicated in staphylococcal scalded-skin syndrome (SSSS). Two antigenically distinct forms, designated ETA and ETB, are the best characterized ETs and are produced most frequently by phage group II by isolates; strains expressing ETs constitute group IV staphylococcal isolates. Lesions in SSSS and mice are characterized by separation of stratum granulosa cells causing intraepidermal skin peeling.

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38

Key Concept Ranking

Major Histocompatibility Complex Class II
Staphylococcal Enterotoxin Type T
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Image of FIGURE 1

Membrane pore formation by alpha-toxin. (A) Rabbit erythrocyte membrane fragment negatively stained following lysis with alpha-toxin. Arrows designate representative ring-shaped structures (10 nm) on the membrane. (B) Ringshaped alpha-toxin multimers isolated in detergent solution. (Inset) The rings are magnified so that the internal channel (2.5 nm) and ring perimeter (10 nm) are clearly visible.

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38
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Image of FIGURE 2

Model for alpha-toxin assembly based on crystallographic data and structure-function experiments. The model depicts the formation of a heptameric ring (α7 and α7*). A cross-section of the ring revealing only four monomers is shown so that the proposed structural alterations are visible. In this model, alpha-toxin is expressed and secreted as a monomer (α1). α1, bound to the target membrane (designated α1*), promotes assembly of the heptamer (α7). In the final stage of assembly, β-sheets in each monomer (depicted as small circles) insert into the membrane, forming a channel, and the N-terminal latches contact adjacent monomers, rendering them resistant to proteolysis.

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38
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Image of FIGURE 3

Properties of staphylococcal beta-toxin. (A) Sphingomyelin chemical formula showing beta-toxin cleavage site resulting in generation of phosphorylcholine and ceramide. (B) Scanning electron micrograph showing lesions in human erythrocyte membranes caused by beta-toxin after shifting the temperature to 4°C.

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38
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Image of FIGURE 4

Molecular aspects of staphylococcal bicomponent toxins. Organization of bicomponent toxin genes in a strain harboring both the and loci. Any S and F component may combine to generate a unique bicomponent toxin. The two prototype bicomponent toxins, PVL and deltatoxin, are composed of LukS-PV+LukF-PV and HlgA+HlgB, respectively.

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38
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Image of FIGURE 5

Structural properties and receptor interactions of PTSAgs. (A) A structural comparison of SEC3 and TSST-1. Ribbon diagrams shown are based on crystal structures published for the two toxins ( ). The two structures are oriented so that the TCR-binding cavity in each is located at the top and the cysteine loop, unique to the SEs, is on the upper right-hand corner of SEC3. Both toxins possess a similar domain organization and an overall topology despite having several important differences as discussed in the text. (B) A model of the trimolecular complex with SEB or SEC bound to TCR and MHC-II (adapted from results of references and ). In this model, SAgs orient the two receptors away from each other, inducing an aberrant mechanism of T-cell activation. Note that antigenic peptide associated with MHC-II is positioned away from the TCR-binding site.

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38
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Image of FIGURE 6

Ribbon diagram of the ETA crystal structure showing important functional features. Similar to other chymotrypsinlike proteases, ETA has two β-barrel domains and a C-terminal α-helix. The N-terminal domain, which includes a highly charged α-helix, is unique and is suspected to be involved in receptor binding. The positions of residues H72, D102, and S195, comprising the putative catalytic triad, are superimposable with the analogous residues of α-thrombin. D164 in loop D controls access of substrate to the protease active site by hydrogen bonding to G193. This causes the P192-G193 peptide bond to flip 180 degrees compared to that seen in other serine proteases and may explain the lack of demonstrable proteolytic activity in vitro. Binding of the N-terminal α-helix to its receptor has been proposed to cause a shift in the position of loop D and thereby the P192-G193 peptide bond, allowing access to the active site in vivo ( ).

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38
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Generic image for table

Reported, confirmed, or potential staphylococcal PTSAgs

SE nomenclature used in this table is that recommended by the International Nomenclature Committee for Staphylococcal Superantigens ( ). Toxins either lacking activity or not yet tested for emetic activity in the primate oral feeding assay are designated staphylococcal enterotoxin-like toxins (SEls), according to standard nomenclature ( ).

ND, not determined or reported.

Weakly emetic ( ).


Originally designated SEK ( ).

Originally designated SEL ( ).

Originally designated SEM ( ).

T-cell stimulation reportedly results from Vα stimulation ( ).

Citation: Bohach G. 2006. Exotoxins, p 464-477. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch38

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