European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Review

Mechanisms of staphylococcal enterotoxin-induced emesis Dong-Liang Hu a, Akio Nakane b,n a b

Department of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan Department of Microbiology and Immunology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan

art ic l e i nf o

a b s t r a c t

Article history: Accepted 3 August 2013

Pathogenic bacteria use various strategies to interact with the host organisms. Among them, toxin production constitutes an efficient way to alter specific functions of target cells. Various enterotoxins interact with the enteric nervous system, by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, diarrhea, or in the intestinal inflammation process. Staphylococcus aureus produces a wide variety of toxins including staphylococcal enterotoxins (SEs) with demonstrated emetic activity; and staphylococcal enterotoxin-like (SEl) proteins, which are not emetic in a primate model or have yet to be tested. SEs and SEls have been traditionally subdivided into classical (SEA to SEE) and new (SEG to SElX) types. These toxins possess superantigenic activity and are highly resistant to denaturation which allows them to remain intact in contaminated foods and trigger food poisoning outbreaks. Symptoms are of rapid onset, and include nausea and violent vomiting. SEA is the most recognizable toxin causing food poisoning in humans throughout the world. However, it remains unclear how SEs induce emesis and via which signal pathway. This review is divided into four parts, and will focus on the following: (1) how bacterial toxins interact with the nervous system, (2) biological characteristics of SEs and SEls, (3) mechanisms of SE-induced emesis, and (4) use of a vaccine for the prevention of SE-induced emesis. & 2013 Elsevier B.V. All rights reserved.

Keywords: Bacterial toxin Staphylococcal enterotoxin Emesis Superantigen Serotonin Mast cell Neuron

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bacterial toxins interacting with the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. Toxins affecting nerve cell inhibition and excitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2. Toxins inducing diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.3. Toxins inducing emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3. Biological characteristics of SEs and SEls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1. Superfamily of classic and new types of SEs and SEls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.2. Molecular structures of SEs and SEls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.3. Resistance of SEs and SEls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.4. Superantigenic activity of SEs and SEls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.5. Emetic activity of SEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4. Mechanisms of SE-induced emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1. Emetic animal models for SEs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.2. Dynamics and target cells of SEs in gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.3. SEs modulate intracellular calcium signaling pathway in intestinal epithelial cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.4. Function of the vagus nerve in SE-induced emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.5. Regulation of type-1 cannabinoid (CB1) receptor in SE-induced emesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5. Use of a vaccine for preventing SE-induced emesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

n

Corresponding author. Tel.: þ 81 172 395032; fax: þ 81 172 395033. E-mail addresses: [email protected] (D.-L. Hu), [email protected] (A. Nakane).

0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.08.050

Please cite this article as: Hu, D.-L., Nakane, A., Mechanisms of staphylococcal enterotoxin-induced emesis. Eur J Pharmacol (2013), http://dx.doi.org/10.1016/j.ejphar.2013.08.050i

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2

1. Introduction Pathogenic bacteria utilize multiple approaches to establish infection, food poisoning and to induce toxicity in eukaryotic cells. Various pathogens employ their toxins to modify host's homeostasis. Most toxins are multifunctional and have the ability to recognize and injure a wider range of cell including intestinal epithelial cells, neuronal cells, hepatocytes and lymphocytes, and thus allow the pathogen access to nutrients. Bacterial exotoxins often target specific cells. For instance, enterotoxins interfere with intestinal epithelial cells (Popoff, 1998), whereas neurotoxins act on neuronal cells leading to neurological symptoms. Bacterial toxins can act locally at the infectious site and/or at the systemic level through circulation, and are responsible for severe diseases in both humans and animals. Bacterial toxins can recognize specific cell surface receptor(s) and/or specific intracellular target(s). When bound to a receptor, toxins can unleash their toxic effects at the cell membrane by interfering with signal transduction pathways, pore formation, or enzymatic activities in the cell membrane (Lubran, 1988). In contrast, some toxins can enter the cytosol, recognize, and modify specific downstream intracellular targets (Lubran, 1988). Intracellularly active toxins cause a dramatic alteration in cellular functions including protein synthesis, cell homeostasis, cell cycle progression, vesicular trafficking, and/ or actin cytoskeletal rearrangement. According to the nature of toxin and the type of target cells, toxins can trigger necrosis or apoptosis in various cell types including neuron. In contrast, some extracellularly active toxins exclusively interact with neuron from the central or peripheral nervous system inducing specific neurological symptoms. Various enterotoxins interact with the enteric nervous system by stimulating afferent neurons or induce neurotransmitter release from enterochromaffin cells which result in vomiting, diarrhea, or intestinal inflammation. Some toxins can pass through the blood–brain barrier and directly act on specific neurons (Caleo and Schiavo, 2009). This review focuses on the pathogenicity of bacterial toxins interacting with nervous system, mainly on staphylococcal enterotoxins (SEs) produced by Staphylococus aureus. Initially we describe the general properties of the bacterial toxins and their interaction with nervous system and consequent diseases. Next, we discuss in detail structures, and biological characteristics of SEs, as well as their mechanism of induction of emesis. Subsequently, we introduce a vaccine for the prevention of SE-induced emesis.

2. Bacterial toxins interacting with the nervous system Some toxins cause pore formation after recognizing ubiquitous membrane components as receptors, such as cholesterol, gangliosides, and proteins. Two unique classes of neurotoxins, botulinum toxin and tetanospasmin, have evolved as specific inhibitors of the neuroexocytotic machinery. These toxins recognize specific receptors on neuronal cells and only interfere with highly specialized intracellular molecules that play a pivotal role in evoked release of neurotransmitters (Caleo and Schiavo, 2009). In addition, bacterial enterotoxins can interact with enterocytes and amplify their intestinal activity by stimulating the secretomotor reflex via the enteric nervous system (ENS), or interact with vagal afferents leading to vomiting (Farthing, 2000). It is noteworthy that the ENS is a preferential target for various bacterial toxins, which transit through the intestinal tract. 2.1. Toxins affecting nerve cell inhibition and excitation Botulinum toxins produced by Clostridium botulinum are very potent neurotoxins and are responsible for neurological disorders

in both humans and animals (Humeau et al., 2000; Lalli et al., 1999; Meunier et al., 2002; Popoff and Poulain, 2010). Botulinum toxins may enter by oral route or they can be produced directly in the intestine subsequent to intestinal colonization of C. botulinum which then undergo a transcytosis across the digestive mucosa (Ahsan et al., 2005; Couesnon et al., 2008; Jin et al., 2009; Maksymowych and Simpson, 1998, 2004; Matsumura et al., 2008). These toxins can target numerous neurons, as well as non-neuronal cells at high concentrations, inhibiting the release of various neurotransmitters including acetylcholine, glutamate, gamma aminobutyric acid (GABA), dopamine, serotonin (5-hydroxytryptomine, 5-HT), substance P, and glycine (Dunant et al., 1987; Foran et al., 2003; McMahon et al., 1992; Najib et al., 1999; Neale et al., 1999; Poulain et al., 1988; Sanchez-Prieto et al., 1987; Smith et al., 2005). Tetanospasmin produced by Clostridium tetani is also potent neurotoxin, which is responsible for neurological disorders in humans and animals. Botulinum toxins and tetanospasmin display a similar intracellular mechanism of action, although they use different routes. Tetanospasmin diffuses in the extracellular fluid and can target many types of nerve endings, but it is mainly retrogradely transported through motoneurons. It inhibits the regulated release of glycine and GABA and disrupts the negative control exerted by the inhibitory interneurons onto motoneurons turning on excessive firing of the motoneurons and ensuing muscle contraction (Deinhardt et al., 2006; Schiavo et al., 2000). Tetanospasmin and botulinum toxins are translocated in different subset of neurons, produce strongly different symptoms and clinical signs (tetanospasmin: spastic paralysis; botulinum toxins: flaccid paralysis). These toxins are representative bacterial toxins that affect inhibition and excitation of nerve cells. 2.2. Toxins inducing diarrhea Increasing evidence suggests that some enterotoxins mediate diarrhea not only by acting directly upon enterocytes, but also by interfering/stimulating the enteric nervous system (Pothoulakis et al., 1998). Cholera toxin (CT) produced by Vibrio cholerae is a pathogenic toxin of a serious epidemic disease characterized by severe diarrhea and dehydration (Asakura and Yoshioka, 1994). CT consists of single A subunit and five B subunits assembled in a pentamer. CT recognizes the glycosphingolipid GM1 on enterocyte membrane, which then is internalized into endocytic vesicles (De Haan and Hirst, 2004). The A fragment of CT is responsible for the enzymatic activities of the toxin, including NAD hydrolysis in ADPribose and nicotinamide, and covalent transfer of ADP-ribose to Arg-187 of the subunit of stimulatory protein Gs leading to stimulation of adenylate cyclase and elevated intracellular cAMP (De Haan and Hirst, 2004). The increased cAMP induces activation of protein kinase A, which subsequently phosphorylates numerous substrates in the cell. This results in an active Cl  secretion and a decrease in NaCl-coupled absorption by enterocytes (De Haan and Hirst, 2004). CT can also stimulate 5-HT release from enterochromaffin cells primarily localized at the base of the epithelial crypts of the intestine, probably via its effect on adenylate cyclase activation (Lundgren, 1998; Turvill et al., 1998). Heat-labile enterotoxin (LT) produced by Escherichia coli is another well known toxin that induces diarrhea in humans and animals. LT does not stimulate the release of 5-HT from enterochromaffin cells, and the diarrhea induced by LT is not inhibited by 5-HT- or substance P-receptor antagonists (Farthing, 2000). However, lignocaine and the ganglionic blocker, hexamethonium, have a preventive effect, suggesting that the ENS is also involved in the enteric activity of LT, but via a distinct pathway than that mediated by 5-HT (Farthing, 2000; Turvill et al., 1998). The heatstable enterotoxin (ST) from E. coli activates guanylate cyclase,

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increases cGMP levels, and subsequently opens Cl  channels. Since ST-induced diarrhea is blocked by tetrodotoxin, lignocaine, hexamethonium and capsaicin and also by vagotomy, the ENS also supports ST activity (Farthing, 2000; Rolfe and Levin, 1999). The exact mechanism of activation of the ENS by ST is still elusive. 2.3. Toxins inducing emesis There are a few bacterial toxins that induce vomiting in humans and animals. Bacillus cereus is a common foodborne pathogen and causes two types of gastrointestinal diseases in humans, diarrhea and emesis (Popoff and Poulain, 2010). Diarrhea is due to enterotoxins, which are multicomponent toxins produced in situ subsequent to excessive proliferation of B. cereus in the small intestine, whereas emesis is caused by ingestion of B. cereus emetic toxin, named cereulide, which accumulates in contaminated foods (Stenfors Arnesen et al., 2008). Cereulide is a cyclic dodecadepsipeptide which is synthesized by nonribosomal peptide synthetase (Agata et al., 1995; Horwood et al., 2004; Toh et al., 2004). It is stable to acid condition, proteolysis and heat, and thus it is not degraded by gastric acid or digestive proteases. Cereulide induces mitochondrial swelling in HEp-2 cells and necrotic cell death in porcine pancreatic Langherans cells (Shinagawa et al., 1995; Shinagawa et al., 1996; Virtanen et al., 2008). It also causes emesis in experimental animal models (Agata et al., 1995; Yokoyama et al., 1999). The mechanism of action of cereulide is only partially known. The emetic effect of cereulide seems to be dependent on stimulation of 5-HT3 receptors on vagal afferent neurons since 5-HT3 receptor antagonists such as ondanserom hydrochloride or vagotomy inhibit the emetic effect in house musk shrew (Agata et al., 1995). However, it is not known whether cereulide directly interacts with vagal sensory endings or releases 5-HT from enterochromaffin cells. Recently, a superfamily of more than 20 different SEs and SElike toxins (SEls), produced by S. aureus, were investigated in detail for their biological activities including emetic activity. These bacterial toxins are known to be pyrogenic and are involved in food poisoning, toxic shock syndrome (TSS) and staphylococcal infectious diseases in humans. In the following sections, we will consider in detail the biological characteristics, molecular structures and the mechanism of SEs-induced emesis.

3

standard nomenclature for the newly discovered toxins (Lina et al., 2004; Thomas et al., 2007). The INCSS naming convention is to emphasize the relevance of the food poisoning (emetic activity). To name the SE, it is required to demonstrate emetic activity via the oral route in a primate model. If an SE exhibits no emetic potential in the vomiting model or its emetic activity is not yet examined, the toxin would be named “staphylococcal enterotoxin-like (SEl) toxin”, even if its structure is closely related to the SEs. In this manner, the addition of 17 new types of SEs or SEls are designated as SEG to SElX in the chronological order of their discovery (Ono et al., 2008; Thomas et al., 2007). To date, the presence of 23 different SEs and SEls have been described (Bergdoll et al., 1959b; Casman, 1960; Ono et al., 2008; Thomas et al., 2007) (Table 1). SEs including SEA–SEE (Balaban and Rasooly, 2000), SEG–SEI (Munson et al., 1998; Su and Wong, 1995), and SER–SET exhibit significant emetic activity in primates (Omoe et al., 2003; Ono et al., 2008). SEls including SElL and SElQ (Orwin et al., 2001; Orwin et al., 2002) are not emetic in the primate model, and other SE1s including SElJ, SElK, SElM–SElP, SElU–SElX (Letertre et al., 2003; Thomas et al., 2006; Wilson et al., 2011) have not been tested yet. There are numerous locations for SE and SEl genes (Argudin et al., 2010; Sato'o et al., 2012). They can be carried Table 1 Biological characteristics of staphylococcal enterotoxins and staphylococcal enterotoxin-like toxins. Toxin Genetic element

SEA SEB SEC1 SEC2 SEC3 SED SEE SEG SEH SEI SElJ

3. Biological characteristics of SEs and SEls

SElK SElL

3.1. Superfamily of classic and new types of SEs and SEls

SElM

S. aureus produces a wide variety of toxins including SEs, SEls and toxic shock syndrome toxin (TSST-1). Since the first characterization of SEA and SEB in 1959 and 1960 by Casman and Bergdoll, five new SEs, SEA to SEE, have been recognized from differences in their antigenicity (Balaban and Rasooly, 2000; Bergdoll et al., 1959b; Casman, 1960). SEC can be further divided into three major antigenic subtypes, SEC1–SEC3 (Balaban and Rasooly, 2000). Todd et al. (1978) had reported that TSS is caused by S. aureus infection through a protein toxin produced by the bacterium. This toxin had been named SEF because its physicochemical properties are very similar to other SEs. However, since SEF does not induce emesis, it was later renamed TSST-1. Thus, SEF is now the missing number. In the late 1990s, the presence of a variety of new SEs began to be revealed. By sequencing the entire genome of S. aureus, genomic DNA library screening, and/or genetic analysis of plasmids and pathogenicity islands, new toxins were discovered one after another, including studies by our research group (Omoe et al., 2003; Ono et al., 2008). In 2004, the International Nomenclature Committee for Staphylococcal Superantigens (INCSS) proposed the

SElN SElO SElP SElQ SER SES SET SElU SElV SElX

Prophage Chromosome, SaPI, plasmid SaPI SaPI SaPI Plasmid (pIB485) Prophage egc, Chromosome, Transposon egc, Chromosome Plasmid (pIB485, pF5) SaPI SaPI egc, Chromosome egc, Chromosome egc, Chromosome Prophage (Sa3n) SaPI Plasmid (pIB485, pF5) Plasmid (pF5) Plasmid (pF5) egc, Chromosome egc, Chromosome Chromosome

Emetic activitya

Molecular weight (kDa)

Mature length (aa)

Superantigenic activity

Monkeyb Suncusc

27.1 28.4

233 239

þ þ

25 100

0.3 10

27.5 27.6 27.6 26.9

239 239 239 233

þ þ þ þ

5 NEd o 50 NE

NEd 1000 NE 40

26.4 27.0

230 233

þ þ

NE 160–320

10 200

25.1 24.9

217 218

þ þ

30 300–600

1000 1

28.6

245

þ

NE

NE

25.3 24.7

219 216

þ þ

NE NE

24.8

217

þ

NE Not emetic NE

26.1

227

þ

NE

NE

26.8

232

þ

NE

NE

26.7

233

þ

NE

50

25.2

216

þ

NE

27.0

233

þ

Not emetic o 100

26.2 22.6 27.2

257 216 256

þ þ þ

o 100 o 100 NE

20 1000 NE

27.6

239

þ

NE

NE

19.3

168

þ

NE

NE

NE

o 1000

þ : Positive reaction. a

μg/animal. Oral administration. c Intraperitoneal administration. d Not examined. b

Please cite this article as: Hu, D.-L., Nakane, A., Mechanisms of staphylococcal enterotoxin-induced emesis. Eur J Pharmacol (2013), http://dx.doi.org/10.1016/j.ejphar.2013.08.050i

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4

by genomic islands (seb, sec, seg, seh, sei, sek, sel, sem, sen, seo, sep and seq), phages (Betley and Mekalanos, 1985; Coleman et al., 1989; Couch et al., 1988), or plasmids (seb, sed, sej, ser, ses, set) (Bayles and Iandolo, 1989; Omoe et al., 2003; Ono et al., 2008; Shalita et al., 1977; Zhang et al., 1998) (Table 1). Gene encoding for SEC can be located on a plasmid or a pathogenicity island depending on the origin of the isolate (Fitzgerald et al., 2001). Enterotoxin gene cluster (egc) can encode for several SEs such as SEG, SEI, SEM, SEN and SEO (Jarraud et al., 2001). This locus probably plays the role of a nursery for se genes, since the phenomena of duplication and recombination from a common ancestral gene may explain new forms of toxins (Letertre et al., 2003; Thomas et al., 2006). SEs and SEls genes located on mobile elements result in horizontal gene transfer between S. aureus isolates (Shafer and Iandolo, 1978). The accessory gene regulator system (agr) is a main regulatory mechanism controlling the expression of virulence factors in S. aureus. This system works in combination with the staphylococcal accessory regulator system (Cheung et al., 1992; Novick et al., 2001). Most but not all of SEs and SEls expression is controlled by the agr system.

SEKSEEINEKDLRKKSELQGT ALGNLKQI YYYNEKAKTEN 20 40 KESHDQFLQHTI LFKGFFTDHSWYNDLLVDFDS KD IVDKY 60 80 KGKKVDLYGAYYGYQCAGGTPNKTACMYGGVTLHDNNRL 100 120 EEKKVPINLWLDGKQNTVPLETVKTNKKNVTVQELDPQAR 140 160 RYLQEKYNLYNSDVFDGKVQRGLI VFHTSTEPS VNYDLFG 200 160 AQGQYSNTLLRIYRDNKTINSENMHIDIYLYTS 220 233 MW: 27,078

3.2. Molecular structures of SEs and SEls

C A significant degree of similarity occurs among the primary peptide sequences of these toxins. These toxins are globular, single-chain proteins, with molecular weights ranging from 19 to 29 kDa (Thomas et al., 2007). They are divided into four phylogenetic groups based on their primary amino acid sequences (Thomas et al., 2007). The toxins recently discovered conform well to the previously defined consensus in terms of conserved residues in the primary sequence (Fig. 1A). Overall, 15% of the residues are entirely conserved throughout the known SEs and SEls (Dinges et al., 2000). Most of these residues are located either centrally or at the C terminus. A great deal of interesting data on the structures of the SEs has been derived from crystallographic studies. The first report dealing with the crystal structure of SEB was made by Swaminathan et al. (1995). SEs conform to a common protein fold. The three-dimensional structures of SEA and SEC have verified this assertion (Fig. 1B) (Dinges et al., 2000; Schad et al., 1995). The overall shape of SE molecules is ellipsoid, and they contain two unequal domains. The secondary structure is a mixture of α-helix and β-sheet components. Domain A contains both the amino and carboxyl termini, as well as a β-grasp motif. The amino-terminal residues drape over the edge of β-sheet in a loosely attached structure. The interfaces between A and B domains are marked by a set of α-helices, which form a long groove in the back side of the molecule and a shallow cavity at the top (Fig. 1B). The domain B is associated with binding to carbohydrates or nucleic acids in other proteins. The internal β-barrel region is richly hydrophobic, and the external surface is covered by a number of hydrophilic residues. The characteristic SE disulfide bond is located at the end of domain B, opposing the α-helical cap. The resulting loop structure is flexible, although this seems to vary among the SEs, depending on the length of the loop. Even though there are some differences in SE structures, the similarities are quite remarkable.

Zn N

Doman A

Doman B

Fig. 1. The complete amino acid sequence (A) and three dimensional structure (B) of SEA.

TSST-1 after treatment with heat, pepsin and trypsin in relation to the condition of food cooking, or luminal location in stomach and intestine (Evans et al., 1983; Li et al., 2011). The superantigenic activity of both SEA and TSST-1 showed marked resistance to heat treatment, pepsin and trypsin digestion. The emetic activity of SEA also showed resistance to these treatments. Although TSST-1 was degraded to smaller fragments after treatment with pepsin or trypsin, it retained significant superantigenic and lethal shock activities relative to those of SEA, indicating such differences may play an important role in the different pathogenic activities of superantigenic toxins during food poisoning and TSS. Their biological properties include induction of high fever similar to bacterial endotoxin induction, lethal shock in animals resulting from excessive intravenous doses, enhanced host susceptibility to endotoxin lethality, cytokine production, and polyclonal T-cell proliferation as seen with other superantigens (Clark and Borison, 1963; Langford et al., 1978).

3.3. Resistance of SEs and SEls 3.4. Superantigenic activity of SEs and SEls SEs and SEls are short secreted proteins that are soluble in water and saline solution. They share common biochemical and structural properties and are remarkably resistant to heat (Dinges et al., 2000). The potency of these toxins can only be gradually decreased by prolonged boiling or autoclaving. They are highly stable and resistant to most proteolytic enzymes, and thus retain their activity in the digestive tract after ingestion. Several groups have compared the respective integrity and toxicity of SEA and

SEs and SEls are representative superantigenic toxins, which selectively activate a vast number of T cells, depending on Vβ elements in the β chain of a T-cell receptor (TCR), in direct association with major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) (Lina et al., 2004; Uchiyama et al., 1994). They subsequently stimulate massive cytokine release and systemic shock (Fig. 2A). A number of studies

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TCR

TCR

C

V

C

J

5

C D

J

1

Antigen peptide

1

2

V

V

J

C

J

1

2

2

MHC class

APC

V 1

2

MHC class II

D

Superantigen

II

APC

TCR binding site

D227 H225

F47

H187 MHC II binding site (1) Doman A

MHC II binding site (2) Doman B

Fig. 2. Diagram of normal antigen (A), superantigen binds to T cell receptor and MHC class II of APC (B), and the binding sites of SEA to these cells (C).

have been undertaken to understand the structural basis for superantigenic activity. Crystallographic and sequence data have allowed some significant advances. These have focused primarily on the binding of SEs to MHC class II molecules on APCs and TCRs (Fields et al., 1996; Labrecque et al., 1994). Based on several mutagenic studies, a general mode of TCR binding has been elucidated. This is in contrast to the well-known Vβ specificity of these molecules. The binding of SEA, SEB, and SEC to TCRs was shown to occur through the shallow cavity at the top of the molecule. SEB and SEC3 (Fields et al., 1996; Li et al., 1998) were crystallized in complex with TCR β-chain, and this complex verified the previously hypothesized contact residues. The contact residues were shown both mutagenically and crystallographically to be from three distantly spaced regions of the primary sequence, which are brought into proximity with each other and TCRs by the protein fold (Hong et al., 1996; Leder et al., 1998). SEB and SEC make contact with TCRs through residues on the top front of the toxin and are hypothesized to bind predominantly outside the binding cleft, allowing for at least some interaction between TCR and the peptide–MHC complex. SEs have evolved several distinct modes of interaction with MHC class II molecules. The information on the SE–MHC interaction was provided by the crystal structure of SEB complexed with MHC class II molecules (Dessen et al., 1997; Jardetzky et al., 1994). Mutations in individual residues responsible for contact between

SEC3 and TCR were made to understand the relationship between TCR binding affinity and mitogenicity. SEA contains two MHC class II binding sites (Fig. 2B). The zinc-dependent site is the major interaction region, and several important residues (H187, H225, and D227) were identified by mutagenesis. It is presumed that this binds MHC β chain (Schad et al., 1995). This major MHC binding site is located in domain A, near the amino terminus (Schad et al., 1995). The second (minor) binding site on SEA is F47 located in domain B, which is not zinc dependent. It may be that cooperation between the two binding sites is responsible for the high affinity of SEA for MHC class II molecules. It could result in a trimer containing the toxin and two bound MHC class II molecules. It has been observed that SED has the potential to form a zincdependent binding site similar to SEA (Fraser, 1993; Hudson et al., 1993). Other toxins such as B. anthracis lethal factor and botulinum toxin have also been found to be proteases and to contain a zinc-binding site. Interestingly, however, no such site is predicted by the structure of SEB (Papageorgiou et al., 1998). The binding of SEB to the MHC–peptide complex was examined by using soluble HLA-DR1 loaded with hemagglutinin peptide HA 306–318. It was found that SEB had a considerably higher affinity for MHC class II molecule, which may well explain the difference in activity (Leder et al., 1998). Mutational studies were done on SEC3 (Leder et al., 1998), and showed that mutations in the TCR binding site of this toxin were capable of sharply reducing

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S. aureus

T cell

SE

TCR

SE SA

Adhesion

Human House musk shrew

MHC II

Monkey APC

IFN- γ TNF- α IL - 2 IL - 6

Interaction with the host cell

Toxic shock

Infection

Inflammation

Serotonin release

Emesis

Fig. 3. The biological multifunctionality of SEs in food poisoning, toxic shock and infection.

mitogenicity. In particular, N23A, Q210A, and F176A had a drastic effect on the mitogenic activity of the toxin. Some mutations caused up to 10-fold reduction in the strength of the interaction (Leder et al., 1998).

3.5. Emetic activity of SEs The first well-documented report that clearly identified SEs as the cause of food poisoning outbreaks, was done by Dack et al. (1930). They isolated a pigment-forming Staphylococcus present in large numbers in a Christmas cake responsible for a food poisoning incident, and sterile culture filtrate of the organism reproduced illness when ingested by human volunteers. Initially, SEA through SEE were identified (Bergdoll et al., 1959a, 1965, 1971; Casman, 1960; Casman et al., 1967) followed by identification and designation of new variants (Lina et al., 2004; Thomas et al., 2007). All SEs, but not SEls, cause emesis when administered to primates orally. Ingestion of SEs does not result in measurable enterotoxemia unless extremely high doses are consumed. SEA is the most common enterotoxin recovered from food poisoning outbreaks in many countries including the United Kingdom (Wieneke et al., 1993), France (Kerouanton et al., 2007), United States of America (Casman, 1965), Brazil (Veras et al., 2008), Korea (Cha et al., 2006) and Japan (Asao et al., 2003; Kitamoto et al., 2009; Shimizu et al., 2000). In contrast to the SEs, orally administered TSST-1 does not cause emesis in monkeys but causes systemic symptom of TSS when given orally to rabbits (Dinges et al., 2000). The target of SEs responsible for initiating the emetic reflex could be located in the abdominal viscera, where putative cellular receptors for SEs exist (Sugiyama and Hayama, 1965). Since these receptors have not yet

been identified, there remains much uncertainty regarding the early events in the pathogenesis of food poisoning. Many different foods can be a good growth medium for S. aureus, and have been implicated in staphylococcal food poisoning, including milk and cream, cream-filled pastries, butter, ham, cheeses, sausages, canned meat, salads, cooked meals and sandwich fillings. The origins of staphylococcal food poisoning differ widely among countries and this may be due to differences in consumption and food habits in each country. In any case, the main sources of contamination are humans (contaminate food handlers via manual contact or via respiratory tract by coughing and sneezing), and contamination can occur after heat treatment of the food. Contamination of food such as raw meat, sausages, raw milk, and raw milk cheese from animal origins is more frequent by animal carriage or infections (e.g., mastitis) (Le Loir et al., 2003). The symptoms of staphylococcal food poisoning are vomiting, abdominal cramps, nausea, sometimes followed by diarrhea after a short period of incubation (Hu et al., 1999, 2003b; Le Loir et al., 2003). In contrast to these well-described clinical manifestations, the physiopathology of symptoms is only partially understood. In conclusion, SEs form a group of serologically distinct, extracellular toxin proteins, that share important properties namely: (1) structural similarities (Dinges et al., 2000); (2) resistance to heat and digestion by pepsin and trypsin (Li et al., 2011); (3) superantigenicity through a noncomplete nonspecific activation of T cells (as each SEs can bind to a subset of Vβ chains) followed by cytokine release and systemic shock (Hu et al., 2003a; Marrack and Kappler, 1990; Papageorgiou and Acharya, 2000); and (4) ability to cause emesis in primate model (Dinges et al., 2000) (Fig. 3).

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peroral administration was found to be 32 μg per kg of body weight, whereas that by intraperitoneal administration was 3 μg per kg. The emetic activity of SEA in house musk shrews was found to be dose-dependent. Multiple emetic episodes occurred during 70 to 108 min after peroral administration of SEA. Similar responses occurred during 65 to 102 min after intraperitoneal injection of SEA (Hu et al., 1999). The animals recovered clinically within 3 h. Death and diarrhea were not seen in the tested animals. Anti-SEA antibody neutralized SEA-induced emesis in these animals. We further investigated the emetic response of shrews to other classic and several new SEs (Hu et al., 2003b). After intraperitoneal administration, all of the SEs caused vomiting in the house musk shrews. Vomiting occurred within 14 to 130 min after intraperitoneal administration. SEE and SEI caused vomiting in house musk shrews in the same dose range as SEA. However, SEC2, SED, SEG, and SEH required relatively higher doses than did SEA, SEE and SEI. Moreover, SEH showed a relatively shorter latency period than did other SEs. It is noteworthy that different types of SEs had different emetic activities in house musk shrews. In monkeys, the doses of SEA, SEB, SEC1, SED, and SEE required to cause emesis by oral or intragastric route have been reported to be between 5 and 100 μg per animal (Table 1) (Bergdoll, 1988). SEs can be classified into four groups according to their amino acid sequences or nucleic acid sequences: SEA group (SEA, SED, SEE, SElJ, SEH, SEN, SEO), SEB group (SEB, SECs, SEG), SEI group (SEI, SElK, SEL, SElM), and SElX group including TSST-1. No definite correlation between the diversity of SEs and the emetic activities was observed, although the SEB group requires relatively high doses to elicit an emetic response. The mechanism of different emetic activities among different types of SEs is still unclear.

4. Mechanisms of SE-induced emesis 4.1. Emetic animal models for SEs Over the past few decades, several studies have been conducted on the nature of SEs and the molecular basis of their superantigen activities (Dinges et al., 2000; Pezato et al., 2012; Pinchuk et al., 2010). However, little is known regarding the mechanisms by which they induce vomiting. Lack of progress in elucidating the mechanism of the emetic activity of SEs can be partially attributed to the lack of convenient and appropriate animal models. The susceptible animal species to develop human-like enterotoxigenic disease are non-human primate models, often, Macaca mulatta (Normann et al., 1969; Stiles and Denniston, 1971). When introduced intragastrically, SEA and SEB have been shown to induce emetic responses and gastrointestinal (GI) inflammatory changes in different Macaca spp. (Merrill and Sprinz, 1968; Reck et al., 1988; Sheahan et al., 1970). Monkeys have been considered to be the primary animal model. Unfortunately, the use of monkeys in investigating SEs is severely restricted by the high cost, the availability of these animals, and ethical considerations. The dog (Kocandrle et al., 1966), pig (Taylor et al., 1982) and piglet (van Gessel et al., 2004) models have been used to reproduce some of the features associated with SEs disease. However, the main disadvantages for use of these models remain the same: high cost and short supply in the available tools for the study of SE associated pathology. Other animals like mouse, rat, rabbit and cat are either less susceptible to SEs, or their responses to SEs are not specific, or they are not vomit-competent species (Bergdoll, 1988). The house musk shrew, Suncus murinus, has been described as a small animal model for the study of emetic response to various emetic drugs (Chen et al., 1997; Okada et al., 1994). The emetic response of house musk shrew to peroral and intraperitoneal administration of SEA has been examined (Hu et al., 2001; Hu et al., 1999) (Table 1, Fig. 4A). The 50% emetic dose (ED50) of SEA by

4.2. Dynamics and target cells of SEs in gastrointestinal tract Abdominal viscera in monkeys have been indicated as the site of emetic action for SEs (Sugiyama and Hayama, 1965). There is no

SEA

basal K+-evoked

granisetron 15 250

10

5-HT release (%)

Frequency of emesis

15

5

0

gran

-

0.3

1

30

30

SEA

+

+

+

+

-

200 150

100 50 0

vehicle

SEA

Fig. 4. The emetic response of house musk shrews against SEA administration. A small emetic animal model, house musk shrews (A, arrow indicates vomit). The emetic response was inhibited by a 5-HT3 receptor antagonist (B, gran; granisetron). SEA induces basal (vehicle) and K þ -evoked 5-HT release in the slices of small intestine (C).

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information concerning these putative receptors for SEs in the abdominal viscera. However, it appears that these receptors exist in the gut of house musk shrew and the differences in affinity between SE types and their receptors might explain the different emetic activities of SE types in this species (Hu et al., 2003b). Ono et al. (2012) investigated the behavior of SEA in GI tract in house musk shrew in vivo. Perorally administered SEA translocated from the lumen to the interior tissues of GI tract and rapidly accumulated in certain submucosa cells. SEA-binding cells in the submucosa were both tryptase- and FcεRIa-positive, suggesting that these cells were mast cells. SEA-binding mast cells were 5-HTpositive, but the intensity of the 5-HT signal decreased over time compared to those mast cells in the negative control group. Furthermore, binding of SEA induced degranulation and release of 5-HT from submucosal mast cells. These observations suggest that submucosal mast cells in GI tract are one of the target cells of SEA and the 5-HT released from submucosal mast cells plays an important role in SEA-induced emesis. We have shown that SEAinduced emesis in the house musk shrew is inhibited by the 5-HT synthesis inhibitor, p-chlorophenylalanine, and the 5-HT3 receptor antagonist, granisetron, showing the important role of 5-HT in SEA-induced emesis (Hu et al., 2007) (Fig. 4B). Some studies have indicated that 5-HT plays a significant role in the early phase of anticancer drug-induced emesis (Minami et al., 2003). The anticancer drugs evoke 5-HT release from enterochromaffin cells, and then stimulates 5-HT receptor on adjacent vagal afferent nerves in the intestine. The resulting depolarization of the vagal afferent nerves stimulates the vomiting center in the medulla oblongata and eventually induces a vomiting reflex (Darmani and Ray, 2009). In addition, SEA-induced emesis is blocked by surgical vagotomy

in house musk shrews and primates (Hu et al., 2007; Sugiyama and Hayama, 1965), suggesting that 5-HT released from submucosal mast cells may bind to 5-HT3 receptor expressed on enteric nerves in GI tract and thereby inducing depolarization of these nerves (Fig. 5). SEA passes through the mucosal epithelium in the GI lumen by an unknown mechanism and then accumulates in the submucosa. This translocation from the lumen to the submucosa occurs within 30–90 min, a timeframe that is consistent with the latency time of SEA-induced emesis in house musk shrew (30–120 min) (Hu et al., 2003b; Hu et al., 1999). In the stomach and duodenum of house musk shrew, SEA binds to the submucosal mast cells or directly to neuron cells. The binding of SEA to an unidentified receptor expressed on the surface of these cells induces the degranulation, resulting in the release of 5-HT. At present, it is unclear what type of molecule acts as an SEA receptor on the surface of submucosal mast cells or neuron cells. Superantigens including SEA bind to MHC class II molecules expressed on surface of APCs. However, SEA and MHC class II signals were not co-localized in the GI tissues of the SEAadministered animals, indicating that a receptor on mast cells is not MHC class II. Moreover, orally administrated SEA shows tendency to bind mast cells rather than MHC class II-positive cells in GI tract, indicating that unidentified SEA receptor on mast cells is capable of binding SEA more efficiently than MHC class II (Ono et al., 2012). Further studies on the identification and molecular cloning of the unidentified SEA receptor gene are necessary for understanding the exact molecular basis of SEA-induced emesis and elucidation of its downstream intracellular signaling. A few studies have shown that SEB binds cultured mast cells and induces the release of mediators such as 5-HT (Komisar et al.,

To brainstem emetic Loci

SEA

Neuron cell

Mast cell

Fig. 5. The putative mechanism of SEA-induced emesis. SEA administered by the peroral route migrates from the GI lumen to submucosa and binds to target submucosal mast cells and/or neurons. The binding of SEA to an unidentified receptor on the surface of the submucosal mast cells then induces 5-HT release. Subsequently, the released 5-HT binds to the 5-HT3 receptor expressed on enteric nerves, and induces depolarization. Finally, the depolarization of the vagal afferent nerves stimulates the brainstem emetic loci to initiate the vomiting reflex.

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1992). Human mast cells are also capable of synthesizing and releasing 5-HT (Kushnir-Sukhov et al., 2007). Based on these results, SEA may also induce degranulation in submucosal mast cells in humans after ingestion of this toxin. Metachromatic mast cells were found in both the mucosa and submucosa in the GI tract. Mast cells exhibit phenotypic heterogeneity in different tissues and play significant roles in a number of important biological events such as IgE-mediated hypersensitivity, innate and adaptive immune response, angiogenesis, and tissue remodeling (Moon et al., 2010). Interestingly, SEA binds only to submucosal mast cells but not mast cells in the lamia propria. It is supposed that the submucosal mast cells are differentiated to act as a target of SEA and play an important role in SEA-induced emesis. Further study of comparative mast cell biology may provide important information for bridging the gap between house musk shrews and humans. 4.3. SEs modulate intracellular calcium signaling pathway in intestinal epithelial cells Little is known about how SEs enter the body via the GI tract and cause food poisoning. Previous studies have shown that SEA does not behave as a bacterial cytotoxin to intestinal epithelial cells (Buxser and Bonventre, 1981). Enterotoxin could cross the intestinal epithelium in immunologically intact form (Hamad et al., 1997) and participate in the initiation, exaggeration or reactivation of enteric inflammatory disease (McKay et al., 2000; McKay and Singh, 1997). To clarify whether SEA can affect any changes in intracellular signaling pathways in intestinal epithelial cells, we performed experiments to demonstrate whether SEA can modulate intracellular calcium ([Ca2 þ ]i) signaling pathway in human intestinal epithelial cells (Hu et al., 2005). The results demonstrated that SEA could induce an increase in [Ca2 þ ]i in intestinal epithelial cells, and the increase originated from intracellular calcium stores. We further investigated the involvement of nitric oxide synthase (NOS) in modifying calcium transients, and showed that SEA-induced [Ca2 þ ]i increase was significantly reduced by NOS inhibitors. The intestinal epithelial cells express endothelial NOS in resting cells and express inducible NOS after being stimulated with tumor necrosis factor (TNF)-α or interferon (IFN)-γ as well as SEA. The cells stimulated with TNF-α showed stronger increases in a Ca2 þ signal, indicating that NOS expression is involved in the [Ca2 þ ]i increase in intestinal epithelial cells evoked by SEA.

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release of proinflammatory molecules or free-radical formation (Hu et al., 2007; Ono et al., 2012). Mucosal terminals of vagal sensory afferent neurons, which project to the emetic loci in the brainstem contain 5-HT3 receptors (Beattie and Smith, 2008). The proposed model includes a SEA-dependent excess release of 5-HT in the intestine and subsequent stimulation of 5-HT3 receptors on vagal afferent neurons triggers emesis (Hu et al., 2007). A specific 5-HT neurotoxin, 5,7-DHT, markedly reduced the emetic response evoked by SEA suggests that the neurons containing 5-HT play a significant role in the mediation of SEA-induced emesis (Hu et al., 2007). Previous studies have shown that 5-HT in the intestinal myenteric plexus stimulates vagal afferent fibers from the stomach and intestine in ferrets and increases vagal nodose ganglia activities in rats (Blackshaw and Grundy, 1993; Glatzle et al., 2002). 5-HT is also present in the central nervous system (Kilpatrick et al., 1987). As 5,7-DHT does not across the blood–brain barrier (Li et al., 2000), it destroys enteric serotonergic neurons selectively and irreversibly when administered intraperitoneally (Gershon et al., 1980; Pineiro-Carrero et al., 1991). Since 5,7-DHT significantly inhibited SEA-induced emesis, it appears that 5-HT released from myenteric plexus neurons and enterochromaffin cells, but not from central neurons, are responsible for the emetic response. This suggestion is further supported by the results of denervation of vagal nerve (Hu et al., 2007; Sugiyama and Hayama, 1965). Both 5,7-DHT and abdominal vagotomy inhibited the SEA-induced emesis, indicating that abdominal vagal afferent nerves seem to be the major pathway for SEA-induced emesis. Recently, it has been demonstrated that Rotavirus infection can trigger 5-HT release from enterochromaffin cells in the intestine leading to activation of vagal afferent nerves connected to brainstem structures associated with vomiting (Hagbom et al., 2011). Rotavirus activated Fos expression in the nucleus of the solitary tract in the brainstem, the main target for incoming fibers from the vagal nerve. Both secreted and recombinant forms of the viral enterotoxin (NSP4), increased intracellular Ca2 þ concentration and released 5-HT from enterochromaffin cells. 5-HT also induced diarrhea in mice within 60 min, thereby supporting the role of 5-HT in the disease. This study provides novel insight into the complex interaction between Rotavirus, enterochromaffin cells, 5-HT and nerves. This signaling pathway is similar to that induced by SEA. 4.5. Regulation of type-1 cannabinoid (CB1) receptor in SE-induced emesis

4.4. Function of the vagus nerve in SE-induced emesis A previous study revealed that SEB-induced effects following its intraperitoneal injection in mice were abrogated by capsaicin which depletes peptidergic sensory nerve fibers and TNF production (Tiegs et al., 1999). An intraperitoneal injection of SEB into rats has been shown to induce Fos expression (a cell activator) throughout the brain via vagal nerve stimulation, thus suggesting that the peripheral presence of SEB has profound effects upon the brain (Wang et al., 2004). Published studies indicate that mast cells play a role in SE-induced food poisoning, which perhaps involves not only inflammatory mediators, but also release of neuropeptides like substance P from sensory neurons (Alber et al., 1989). More recently, it has been reported that SEA-induced emesis is mediated by 5-HT. Indeed, emesis caused by SEA in house musk shrew is inhibited by both a 5-HT synthesis inhibitor and a 5-HT3 receptor antagonist (Hu et al., 2007). In addition, SEA increases 5-HT release in the intestine (Hu et al., 2007; Ono et al., 2012). The mechanism of 5-HT release mediated by SEA is not yet known. SEA might interact directly with enterochromaffin cells or neurons to trigger 5-HT release, or could act indirectly through the

Type-1 cannabinoid (CB1) receptor is expressed in high abundance in diverse brain regions including the brainstem, stomach and intestine in house musk shrews (Hu et al., 2007). SEA induced emesis can be suppressed by cannabinoid CB1/2 receptor agonists, and the inhibition was reversed by AM251, a CB1 receptor selective antagonist. Similar antiemetic efficacy for structurally diverse CB1/ 9 2 receptor agonists (Δ -THC; WIN55-212-2, CP55,940 and HU210) have been demonstrated against diverse emetogens (e.g., 5-HT3 receptor agonists, dopamine D2/3 receptor agonists, cisplatin, radiation) in ferrets, house musk shrews or least shrews (Cryptotis parva) (Darmani and Ray, 2009). Both CB1 receptor agonists and 5HT3 receptor antagonists can reproduce similar behavioral effects such as non-opioid analgesia, anti-emesis in cancer patients and are involved in mood and drug abuse (Greenshaw, 1993; Howlett et al., 1990). 5-HT3 receptors may be involved in the antiemetic action of CB1 receptor agonists. In fact CB1/2 receptor agonists can suppress 5-HT3-receptor mediated currents in the nodose ganglion in a noncompetitive mannor (Fan, 1995). Indeed, Δ9-THC pretreatment can prevent vomiting caused by administration of 5HT3 receptor agonists in the least shrew in a CB1 receptor-dependent

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manner (Darmani and Johnson, 2004). Moreover, the CB1 receptor antagonist SR141716A, can induce vomiting in the latter species via release of serotonin in the brainstem (Darmani, 2001; Darmani et al., 2003). Administration of a CB1 receptor agonist has been shown to significantly attenuate SEA-induced 5-HT release in the intestine (Hu et al., 2007). These results suggest that the effect of a cannabinoid receptor agonists on SEA-induced emesis is mediated via CB1 receptor on enteric nerves as well as the brainstem. The CB1 receptor is a G protein-coupled receptor that can inhibit adenylate cyclase, inactivate A-type K þ channels, and inhibit transmitter release by the direct binding of the β/γ-subunit of G protein to calcium channels in the post-synaptic membrane (Kreitzer et al., 2002). Studies have shown that the activation of CB1 receptor inhibits the release of noradrenaline in human and guinea pig brain (Schlicker et al., 1997) and dopamine release in rat brain in vitro (Cadogan et al., 1997). 5-HT release in the mouse brain cortex is also inhibited via presynaptic CB1 receptors (Nakazi et al., 2000). Nervemuscle preparations of guinea pig small intestine respond to CB1 receptor agonists with an inhibition of electrically evoked contraction, believed to be the results of diminished release of neurotransmitters (Pertwee, 2001). Thus, the overall published data indicate that CB1 receptor agonists inhibit SEA-induced emesis through a reduction in 5-HT release in the small intestine (Hu et al., 2007). These results may have important implications for the pathogenesis of food poisoning.

5. Use of a vaccine for preventing SE-induced emesis Although the molecular basis of the superantigenic activities of SEs has been extensively studied, little is known about the mechanism by which these toxins induce symptoms of food poisoning, which in turn hampers the design of protective antiemetic measures (Hamad et al., 1997; McKay, 2001). The lack of progress in identifying a mechanism and studying the protective measures of the emetic activity of SEs is partially attributed to the lack of a rodent model for toxin-mediated food poisoning (Hamad et al., 1997; Hu et al., 2003b). To shed some light on the problem of the protective measures of SE-induced emesis, one current research prepared a nontoxic mutant of SEA, SEAD227A, and investigated whether its vaccination could protect against SEA induced vomiting in the house musk shrews (Hu et al., 2009). The results showed that SEAD227A is devoid of both superantigenic and emetic activities, but still retains immunoreactivity. Immunization with SEAD227A significantly protected against SEA-induced emesis in house musk shrews, and the antiserum from the immunized shrews showed potent neutralizing activity against both superantigenic and emetic activities of SEA in vitro and in vivo, suggesting that this nontoxic mutant vaccine can prevent staphylococcal food poisoning induced by S. aureus. SEAD227A is highly effective in inducing toxin-specific antibodies capable of neutralizing superantigenicity and protecting animals from SEA-induced emesis. The mechanism of action of serum antibodies in enterotoxin induced vomiting in vivo remains elusive. One of the demonstrated effects of antibodies is antiinflammatory activity (LeClaire et al., 2002; Schlievert, 2001), and another is neutralization of the toxicity of superantigenic toxins (Nilsson et al., 1998). Some studies have identified cross-reactive antibodies between SEs and streptococcal pyrogenic exotoxin A (Bohach et al., 1988; Meyer et al., 1984). Recently, it was reported that anti-TSST-1 antibody also cross-inhibited SEA-induced mitogenic activity and TNF-α production in vitro and protected against SEA-induced lethality in a mouse model (Kum and Chow, 2001). SEA-specific antibodies might play an important role in neutralization of superantigenic activity as well as host resistance against toxin-induced emesis (Hu et al., 2009). Because the expression of

SEs is common among invasive S. aureus strains and food poisoning isolates, the nontoxic SEAD227A and the antibodies might be useful in the control of staphylococcal food poisoning and the treatment of foodborne diseases.

6. Conclusions Bacterial toxins interact with various cells of human and animal origin. Some bacterial toxins recognize ubiquitous membrane components as receptors, and indiscriminately damage membranes from different cells, including those of neuronal origin. Some toxins have developed various internalization processes, and specifically modify an intracellular target. Neurotoxins such as botulinum toxin and tetanospasmin, recognize specific receptors on neuronal cells and only interfere intracellularly with highly specialized molecules which play a pivotal role in the evoked release of neurotransmitter(s). Various bacterial enterotoxins specifically interact with enterocytes, and subsequently amplify intestinal activity by stimulating the secretomotor reflex of the ENS, like CT, or interact with distinct neuronal afferents from the intestinal mucosa leading to vomiting. It is noteworthy that the ENS is a preferential target for many bacterial toxins, which transit through the intestinal tract. SEs produced by S. aureus belong to the fascinating family of superantigens which induce potent emesis and are involved in toxic shock as well as infection. Members of the family are well characterized with regard to superantigenic activity. However, the bases for the enterotoxigenic and emetic activities associated with a number of S. aureus superantigens remain elusive. Modes of action for the enterotoxins reviewed here have been deciphered during the last decade, and now a picture of their target cells and potential signaling pathway is emerging. The mutant vaccine and the specific antibody of SEA have enabled them to become useful tools to prevent SEs-induced food poisoning. However, additional studies are needed to identify their specific membrane-receptors, as well as comprehending the mechanisms and structures involved in toxin routing throughout the nervous system. Thus, multidisciplinary approaches integrating molecular microbiology, membrane biology, biochemistry, physiology, proteomics and pharmacology will further advance our understanding of the emetic mechanisms required for directing molecules to specific locations within the GI and nervous system of humans and animals. References Agata, N., Ohta, M., Mori, M., Isobe, M., 1995. A novel dodecadepsipeptide, cereulide, is an emetic toxin of Bacillus cereus. FEMS Microbiol. Lett. 129, 17–20. Ahsan, C.R., Hajnoczky, G., Maksymowych, A.B., Simpson, L.L., 2005. Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cells. J. Pharmacol. Exp. Ther. 315, 1028–1035. Alber, G., Scheuber, P.H., Reck, B., Sailer-Kramer, B., Hartmann, A., Hammer, D.K., 1989. Role of substance P in immediate-type skin reactions induced by staphylococcal enterotoxin B in unsensitized monkeys. J. Allergy Clin. Immunol. 84, 880–885. Argudin, M.A., Mendoza, M.C., Rodicio, M.R., 2010. Food poisoning and Staphylococcus aureus enterotoxins. Toxins (Basel) 2, 1751–1773. Asakura, H., Yoshioka, M., 1994. Cholera toxin and diarrhoea. J. Gastroenterol. Hepatol. 9, 186–193. Asao, T., Kumeda, Y., Kawai, T., Shibata, T., Oda, H., Haruki, K., Nakazawa, H., Kozaki, S., 2003. An extensive outbreak of staphylococcal food poisoning due to low-fat milk in Japan: estimation of enterotoxin A in the incriminated milk and powdered skim milk. Epidemiol. Infect. 130, 33–40. Balaban, N., Rasooly, A., 2000. Staphylococcal enterotoxins. Int. J. Food Microbiol. 61, 1–10. Bayles, K.W., Iandolo, J.J., 1989. Genetic and molecular analyses of the gene encoding staphylococcal enterotoxin D. J. Bacteriol. 171, 4799–4806. Beattie, D.T., Smith, J.A., 2008. Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedebergs Arch. Pharmacol. 377, 181–203. Bergdoll, M.S., 1988. Monkey feeding test for staphylococcal enterotoxin. Methods Enzymol. 165, 324–333.

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Please cite this article as: Hu, D.-L., Nakane, A., Mechanisms of staphylococcal enterotoxin-induced emesis. Eur J Pharmacol (2013), http://dx.doi.org/10.1016/j.ejphar.2013.08.050i

Mechanisms of staphylococcal enterotoxin-induced emesis.

Pathogenic bacteria use various strategies to interact with the host organisms. Among them, toxin production constitutes an efficient way to alter spe...
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