Chapter 11 : Toxins of

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This chapter reviews new information about cholera enterotoxin (CT) and about recently discovered toxins produced by . The single tryptophan residue (Trp-88) in each subunit is essential for binding, as shown by chemical modification and site-directed mutagenesis studies. The majority of the experiments described in the chapter have been performed in vivo, and the results often differ from those obtained in in vitro experiments examining the role of the enteric nervous system (ENS). Several additional toxins produced by are discussed, such as hemolysin-cytolysin, zonula occludens toxin (Zot), accessory cholera enterotoxin and miscellaneous toxins. Stable enterotoxin (ST) and thermostable direct hemolysin (TDH), have well-established mechanisms of enterotoxicity but are rarely produced by . Two of the toxins, the sodium channel inhibitor and the "new cholera toxin" (NCT) of Sanyal and coworkers, are insufficiently characterized to access their potential roles in disease. The three non-CT toxins that are the best characterized are the hemolysin-cytolysin, Zot, and Ace. The study of CT has produced profound insights into the pathogenesis, treatment, and prevention of cholera. Furthermore, it has yielded knowledge on basic cellular functions and structures such as intracellular messengers and neurological pathways. The study of toxins other than CT has demonstrated new potential mechanisms of diarrhea and may also produce new insights into basic cellular functions such as the assembly and regulation of tight junctions.

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11

Key Concept Ranking

Small Intestine
Adenylate Cyclase Toxin
Immune Systems
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Image of Figure 1
Figure 1

Crystal structure of the LT holotoxin shown as a ribbon plot. The A subunit shown at the top is connected to the В pentamer via the long helical structure of the A peptide. Reprinted from with permission ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Image of Figure 2
Figure 2

(A) Ribbon plot of the structure of the LT A subunit showing the triangular shape of the A peptide (top right) and the long helix (left) of A, terminated by a single small helix and tail. (B) Schematic secondary structure diagram of the В pentamer. A single В subunit is shown in light gray. Reprinted from with permission ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Image of Figure 3
Figure 3

Mode of action of CT; see text for details. (A) Adenylate cyclase, located in the basolateral membrane of intestinal epithelial cells, is regulated by G proteins. CT binds via the B-subunit pentamer to the GM ganglioside receptor inserted into the lipid bilayer. (B) The A subunit enters the cell, perhaps via endosomes, and is proteolytically cleaved, with subsequent reduction of the disulfide bond to yield A and A peptides. The A peptide is activated (at least in vitro) by ARF and transfers an ADP-ribose moiety (ADPR) and NAD to the subunit of the G protein. The ADP-ribosylated subunit dissociates from the other subunits of G and activates adenylate cyclase, thereby increasing the intracellular сAMP concentration. Three possible scenarios have been proposed to explain entry of the toxin and activation of adenylate cyclase. Possibility 1 proposes that the A subunit translocates through the apical membrane, leaving the В pentamer on the apical membrane. The A diffuses freely through the cytoplasm to the basolateral membrane, where it ADP-ribosylates G . Possibility 2 is that the A peptide ADP-ribosylates an subunit in the apical membrane. The ADP-ribosylated subunit traverses the cell to attach to the adenylate cyclase located in the basolateral membrane. Possibility 3 is that the entire toxin enters the cell via endosomes and the A subunit translocates through the endosomal membrane. The endosome travels through the cell with the A peptide still associated with the endosomal membrane. The A peptide ADP-ribosylates the G, located in the basolateral membrane, perhaps after an endosome-plasma membrane fusion. (C) Increased cAMP activates protein kinase A, leading to protein phosphorylation. Protein phosphorylation leads to increased Cl secretion in crypt cells and decreased NaCl-coupled absorption in villus cells.

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Figure 4

Arrangement of and genes in the core region. RS1 elements are shown on both sides of the core region, a common arrangement in El Tor but not classical strains. The enlarged regions depict the overlapping open reading frames of and and of and . In addition, the region where the stop codon of overlaps the first ToxR binding repeat upstream of the operon is also enlarged. Also shown are an open reading frame of unknown function, and (core-encoded pilus), the gene for a recently described colonization factor ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Figure 5

Electron micrograph showing the entry of wheat germ agglutinin-horseradish peroxidase into the para-cellular space of rabbit ileal cells exposed for 60 min to medium (A) or to culture supernatants of Zot CVD101 (B). Taken from Fasano et al. ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Image of Figure 6
Figure 6

Freeze-fracture studies of rabbit ileal tissue showing effect of culture supernatants of on ZO. (A) An intact ZO with numerous intersections (arrowheads) between junctional strands. MV, microvilli. (B) An affected ZO from ileal tissue exposed to culture supernatants of 395. Taken from Fasano et al. ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Figure 7

Amino acid sequence comparison of the predicted ace gene product and predicted sequence of two ion-transporting ATPases, the human plasma membrane Ca pump (CaPM) and the Ca-transporting ATPase from rat brain (RPMCA); a virulence protein in (SpvB); and the CF transmembrane conductance regulator (CFTR). Boxes indicate identical or similar amino acid residues in Ace and the other sequences. Ace was aligned separately with CFTR to maximize sequence similarity. Taken from Trucksis et al. ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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Image of Figure 8
Figure 8

Potential amphipathic region of Ace. The C-terminal end of the Ace protein containing a predicted a helix is arranged in the form of a wheel to show the predominance of hydrophobic (boxed) residues on one side of the helix. The glutamine (Q) at the top of the wheel is residue 76 of the predicted amino acid sequence of Ace. Taken from Trucksis et al. ( ).

Citation: Kaper J, Fasano A, Trucksis M. 1994. Toxins of , p 145-176. In Wachsmuth I, Blake P, Olsvik Ø (ed), and Cholera. ASM Press, Washington, DC. doi: 10.1128/9781555818364.ch11
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