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13 Bacterial Toxins

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Abstract:

This chapter discusses the molecules that have been classically known as bacterial toxins; the last section mentions some recently identified molecules that cause cell intoxication and have many but not all of the properties of classical toxins. A section shows the subunit composition and the spatial organization of toxins whose structures have been solved either by X-ray crystallography or by quick-freeze deep-etch electron microscopy. For simplicity, the toxins have been divided into three main categories: (i) those that exert their powerful toxicity by acting on the surface of eukaryotic cells simply by touching important receptors, by cleaving surface-exposed molecules, or by punching holes in the cell membrane, thus breaking the cell permeability barrier; (ii) those that have an intracellular target and hence need to cross the cell membrane (these toxins need at least two active domains, one to cross the eukaryotic cell membrane and the other to modify the toxin target); and (iii) those that have an intracellular target and are directly delivered by the bacteria into eukaryotic cells. Depending on their target, these toxins can be divided into different groups that act on protein synthesis, signal transduction, actin polymerization, and vesicle trafficking within eukaryotic cells. The toxins that inhibit protein synthesis, causing rapid cell death, at extremely low concentrations are diphtheria toxin (DT), exotoxin A (ExoA), and Shiga toxin.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13

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Toxic Shock Syndrome Toxin 1
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Figures

Image of Figure 13.1
Figure 13.1

Structural features of bacterial toxins whose structures have been solved. (Left) Scheme of the primary structure of each toxin. For the A/B toxins, the domain composition is also shown. The A (or S1 in PT) represents the catalytic domain, whereas the B represents the receptor-binding domain. The A subunit is divided into the enzymatically active A1 domain and the A2 linker domain in Shiga toxin, CT, LT-I and LT-II, and PT. The B domain has either five subunits, which are identical in Shiga toxin, CT, and LT-I and LT-II and different in size and sequences in PT, or two subunits, the translocation (T) and the receptor-binding (R) subunits, in DT, exotoxin A, botulinum toxin, and tetanus toxin. (Right) Schematic representation of the three-dimensional organization of each toxin. For enterotoxin B, the protein is shown in the ternary complex with the human class II histocompatibility complex molecule (DR1) and the T-cell antigen receptor (TCR). For SptP the structure is shown in the transition state complex with the small GTP-binding protein Rac1. Similarly, toxin SopE is represented in complex with its substrate Cdc42. In the case of CNF1 and ExoS, only one domain has been crystallized. In the case of SipA, a three-dimensional reconstruction of SipA bound to F-actin filaments is also reported. For all toxins the schematic representation is based on the X-ray structure, except that for VacA, whose structure has been solved by quick-freeze, deep-etch electron microscopy.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Image of Figure 13.2
Figure 13.2

Morphology changes induced by toxins in cell lines. Untreated cells (left) and toxin-treated cells (right). Abbreviations: NIH3T3-PT, NIH 3T3 cells treated with pertussis toxin; CHO-PT, Chinese hamster ovary cells treated with pertussis toxin; CHO-CT, Chinese hamster ovary cells treated with cholera toxin; Y1-CT, Y1 cells treated with CT; HeLa-VacA, HeLa cells treated with vacuolating cytotoxin A; Vero-DT, Vero cells treated with DT; Vero-Shiga toxin, Vero cells treated with Shiga toxin. Photographs from our laboratory or kindly provided by Ida Luzzi, Istituto Superiore di Sanità, Rome, Italy. Immunofluorescence micrograph of untreated or toxin-treated Vero cells. Abbreviations: EcCNF1, cytotoxin-necrotizing factor; Cb exoenzyme C3, C3; CdB, cytotoxin B; CsLT, lethal toxin. Cells were stained with palloidin-fluorescein to visualize F-actin. Photographs kindly provided by Patrice Boquet, INSERM, Nice, France.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Image of Figure 13.3
Figure 13.3

Schematic representation of the four groups of bacterial toxins. Group 1 toxins act by binding receptors on the cell membrane and sending a signal to the cell. Group 2 toxins act by forming pores in the cell membrane, perturbing the cell permeability barrier. Group 3 toxins are A/B toxins, composed of a binding domain (B subunit) and an enzymatically active effector domain (A subunit). Following receptor binding, the toxins are internalized and located in endosomes, from which the A subunit can be transferred directly to the cytoplasm by using a pH-dependent conformational change (3.1) or can be transported to the Golgi and the ER (sometimes driven by the KDEL ER retention sequence), from which the A subunit is finally transferred to the cytoplasm (3.2). Group 4 toxins are injected directly from the bacterium into the cell by a specialized secretion apparatus (type III or type IV secretion system).

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Figure 13.4

Schematic representation of the interaction of superantigens with the MHC class II molecule and T-cell receptor.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Image of Figure 13.5
Figure 13.5

Schematic representation of membrane interaction and oligomerization of large-pore-forming toxins and small-pore-forming toxins In the case of large-pore-forming toxins, the prepore intermediate state is also shown. The dimension of the final pore can reach 35 nm, and up to 50 monomers can be involved.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Image of Figure 13.6
Figure 13.6

Mechanism of PA-mediated entry and intoxication of anthrax LF and EF toxins.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Image of Figure 13.7
Figure 13.7

Catalytic and NAD-binding site of ADP-ribosylating toxins. Diagram of the three-dimensional structure of the catalytic site of DT and LT showing the NAD molecule (gold) inside the cavity and the two amino acids, Glu and Arg/His, important for catalysis. Schematic representation of the catalytic site of PT showing the NAD and the two catalytic amino acids which have been mutagenized to generate the genetically detoxified PT9K/129G mutant.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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Image of Figure 13.8
Figure 13.8

Scheme of a postsynaptic membrane showing the normal process of neurotransmitter (NT) release (left) and the mechanism of action of the neurotoxins (right). Vesicles containing the neurotransmitter have a transmembrane protein (synaptobrevin or v-SNARE) that binds specifically two proteins enclosed on the cell membrane (syntaxin, SNAP-25, or t-SNARE). The initial interaction becomes increasingly stronger, forcing the vesicle and cellular membranes to become in close contact and finally to fuse, thus releasing the neurotransmitters into the intercellular space. The mechanism of action of tetanus and botulinum neurotoxins is shown on the right. They cleave the v-SNARE and/or the t-SNARE, thus preventing the docking and fusion of neurotransmitter-containing vesicles.

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
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References

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1. Alouf, J. E.,, and J. R. Freer (ed.). 1999. The Comprehensive Sourcebook of Bacterial Protein Toxins. Academic Press, London, United Kingdom. A fundamental reading for a comprehensive knowledge of major bacterial toxins and their implications in cell biology and vaccine design.
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11. Pallen, M. J.,, A. C. Lam,, N. J. Loman,, and A. McBride. 2001 An abundance of bacterial ADP-ribosyltransferases: implications for the origin of exotoxins and their human homologues. Trends Microbiol. 9:302307.
12. Pellizzari, R.,, C. Guidi-Rontani,, G. Vitale,, M. Mock,, and C. Montecucco. 2000. Lethal factor of Bacillus anthracis cleaves the N-terminus of MAPKKs: analysis of the intracellular consequences in macrophages. Int. J. Med. Microbiol. 290:421427.
13. Pizza, M.,, A. Covacci,, A. Bartoloni,, M. Perugini,, L. Nencioni,, M. T. De Magistris,, L. Villa,, D. Nucci,, R. Manetti,, M. Bugnoli,, F. Giovannoni,, R. Olivieri,, J. T. Barbieri,, H. Sato,, and R. Rappuoli. 1989. Mutants of pertussis toxin suitable for vaccine development. Science 246:497500. This publication describes the genetic inactivation of pertussis toxin (PT), which will be used as a principal component of the first acellular vaccine against pertussis.
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Tables

Generic image for table
Table 13.1

Bacterial toxins and their targets: update

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13
Generic image for table
Table 13.2

Large-pore-forming toxins

Citation: Pizza M, Masignani V, Rappoulli R. 2004. 13 Bacterial Toxins, p 299-340. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch13

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