Document Detail

Food poisoning and Staphylococcus aureus enterotoxins.
Jump to Full Text
MedLine Citation:
PMID:  22069659     Owner:  NLM     Status:  MEDLINE    
Staphylococcus aureus produces a wide variety of toxins including staphylococcal enterotoxins (SEs; SEA to SEE, SEG to SEI, SER to SET) with demonstrated emetic activity, and staphylococcal-like (SEl) proteins, which are not emetic in a primate model (SElL and SElQ) or have yet to be tested (SElJ, SElK, SElM to SElP, SElU, SElU2 and SElV). SEs and SEls have been traditionally subdivided into classical (SEA to SEE) and new (SEG to SElU2) types. All possess superantigenic activity and are encoded by accessory genetic elements, including plasmids, prophages, pathogenicity islands, vSa genomic islands, or by genes located next to the staphylococcal cassette chromosome (SCC) implicated in methicillin resistance. SEs are a major cause of food poisoning, which typically occurs after ingestion of different foods, particularly processed meat and dairy products, contaminated with S. aureus by improper handling and subsequent storage at elevated temperatures. Symptoms are of rapid onset and include nausea and violent vomiting, with or without diarrhea. The illness is usually self-limiting and only occasionally it is severe enough to warrant hospitalization. SEA is the most common cause of staphylococcal food poisoning worldwide, but the involvement of other classical SEs has been also demonstrated. Of the new SE/SEls, only SEH have clearly been associated with food poisoning. However, genes encoding novel SEs as well as SEls with untested emetic activity are widely represented in S. aureus, and their role in pathogenesis may be underestimated.
María Ángeles Argudín; María Carmen Mendoza; María Rosario Rodicio
Related Documents :
21770849 - Review of mycotoxin reduction in food and feed: from prevention in the field to detoxif...
17684199 - Methylphenidate reduces energy intake and dietary fat intake in adults: a mechanism of ...
17578259 - Partitioning of late gestation energy expenditure in ewes using indirect calorimetry an...
8968859 - Estimated energy balance in female university students: differences with respect to bod...
9023599 - The effect of sucrose- and aspartame-sweetened drinks on energy intake, hunger and food...
17292929 - Effects of a combination fiber system on appetite and energy intake in overweight humans.
3041449 - Food-associated intoxicants.
2729159 - Dietary modulation of the progression of nephropathy in aging rats: an evaluation of th...
6786129 - Oral and inhaled sodium cromoglycate in challenge test with food allergens or acetylsal...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2010-07-05
Journal Detail:
Title:  Toxins     Volume:  2     ISSN:  2072-6651     ISO Abbreviation:  Toxins (Basel)     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2011-11-09     Completed Date:  2013-04-30     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101530765     Medline TA:  Toxins (Basel)     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  1751-73     Citation Subset:  IM    
Department of Functional Biology (Section of Microbiology) and University Institute of Biotechnology of Asturias (IUBA), University of Oviedo, Oviedo, Spain.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Bacterial Toxins / metabolism,  toxicity*
Enterotoxins / metabolism,  toxicity*
Staphylococcal Food Poisoning / etiology*
Staphylococcus aureus / chemistry,  metabolism,  pathogenicity*
Superantigens / metabolism,  toxicity*
Reg. No./Substance:
0/Bacterial Toxins; 0/Enterotoxins; 0/Superantigens

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Toxins (Basel)
Journal ID (publisher-id): toxins
ISSN: 2072-6651
Publisher: MDPI
Article Information
Download PDF
© 2010 by the authors; licensee MDPI, Basel, Switzerland
Received Day: 03 Month: 5 Year: 2010
Revision Received Day: 24 Month: 6 Year: 2010
Accepted Day: 30 Month: 6 Year: 2010
Electronic publication date: Day: 05 Month: 7 Year: 2010
collection publication date: Month: 7 Year: 2010
Volume: 2 Issue: 7
First Page: 1751 Last Page: 1773
ID: 3153270
PubMed Id: 22069659
DOI: 10.3390/toxins2071751
Publisher Id: toxins-02-01751

Food Poisoning and Staphylococcus aureus Enterotoxins
María Ángeles Argudín
María Carmen Mendoza
María Rosario Rodicio*
Department of Functional Biology (Section of Microbiology) and University Institute of Biotechnology of Asturias (IUBA), University of Oviedo, Oviedo, Spain; Email: (M.A.A.); (M.C.M)
* Author to whom correspondence should be addressed; Email:; Tel.: +34-985-103-560; Fax: +34-985-103-534.

1. Staphylococcal Food Poisoning

Staphylococcal food poisoning (SFP) is an intoxication that results from the consumption of foods containing sufficient amounts of one (or more) preformed enterotoxin [1,2]. Symptoms of SFP have a rapid onset (2–8 h), and include nausea, violent vomiting, abdominal cramping, with or without diarrhea [3,4,5]. The disease is usually self-limiting and typically resolves within 24–48 h after onset. Occasionally it can be severe enough to warrant hospitalization, particularly when infants, elderly or debilitated people are concerned [4].

Food handlers carrying enterotoxin-producing S. aureus in their noses or on their hands are regarded as the main source of food contamination, via manual contact or through respiratory secretions. In fact, S. aureus is a common commensal of the skin and mucosal membranes of humans, with estimates of 20–30% for persistent and 60% for intermittent colonization [6]. Because S. aureus does not compete well with indigenous microbiota in raw foods, contamination is mainly associated with improper handling of cooked or processed foods, followed by storage under conditions which allow growth of S. aureus and production of the enterotoxin(s). However, S. aureus is also present in food animals, and dairy cattle, sheep and goats, particularly if affected by subclinical mastitis, are likely contaminants of milk [7]. Air, dust, and food contact surfaces can also serve as vehicles in the transfer of S. aureus to foods.

Foods that have been frequently incriminated in staphylococcal intoxication include meat and meat products, poultry and egg products, milk and dairy products, salads, bakery products, particularly cream-filled pastries and cakes, and sandwich fillings [8,9]. Salted food products, such as ham, have also been implicated [10], according to the capacity of S. aureus to grow at relatively low water activity (aw = 0.86; [11]).

SFP is a common disease whose real incidence is probably underestimated for a number of reasons, which include misdiagnosis, unreported minor outbreaks, improper sample collection and improper laboratory examination. The control of this disease is of social and economic importance. In fact, it represents a considerable burden in terms of loss of working days and productivity, hospital expenses, and economical losses in food industries, catering companies and restaurants [2,3,12,13,14,15].

2. Staphylococcus aureus Enterotoxins

The S. aureus enterotoxins (SEs) are potent gastrointestinal exotoxins synthesized by S. aureus throughout the logarithmic phase of growth or during the transition from the exponential to the stationary phase [16,17,18,19,20]. They are active in high nanogram to low microgram quantities [21], and are resistant to conditions (heat treatment, low pH) that easily destroy the bacteria that produce them, and to proteolytic enzymes, hence retaining their activity in the digestive tract after ingestion [22,23,24].

2.1. Nomenclature

SEs belong to the broad family of pyrogenic toxin superantigens (SAgs; [3]). SAgs bypass conventional antigen recognition by interaction with major histocompatibility complex (MHC) class II molecules on the surface of antigen presenting cells, and with T-cell receptors (TCR) on specific T-cell subsets. Interaction typically occurs to the variable region of the TCR β chain (Vβ) but binding to the TCR Vα domain has been reported [21,25,29]. This leads to activation of a large number of T-cells followed by proliferation and massive release of chemokines and proinflammatory cytokines that may led to potentially lethal toxic shock syndrome [3]. However, staphylococcal enterotoxins have been proposed to be named according to their emetic activities [30]. Only SAgs that induce vomiting after oral administration in a primate model will be designated as SEs. Related toxins that lack emetic activity or have not been tested for it should be designated as staphylococcal enterotoxin-like (SEls) SAgs. Also, newly discovered toxins with more than 90% amino acid sequence identity with existing SEs or SEls should be designated as a numbered subtype. However, despite this consensus nomenclature some subtypes are still just called variants.

At the time of this review, the repertoire of S. aureus SEs/SEls comprised 22 members, excluding molecular variants: (i) the classical SEA, SEB, SEC (with the SEC1, SEC2 and SEC3, SEC ovine and SEC bovine variants), SED and SEE, which were discovered in studies of S. aureus strains involved in SFP outbreaks, and classified in distinct serological types [31,32,33,34,35]; and (ii) the new types of SEs (SEG, SEH, SEI, SER, SES, SET) and SEls (SElJ, SElK, SElL, SElM, SElN, SElO, SElP, SElQ, SElU, SElU2, and SElV) [28,36,37,38,39,40,41,42,43,44,45]. TSST-1, the toxic shock staphylococcal toxin, initially designated as SEF, lacks emetic activity [46,47].

2.2. Structure

SEs and SEls constitute a family of structurally related exoproteins that range in size from ~22 to 28 kDa (Table 1). Based on amino acid sequence comparisons, they have been distributed into four or five groups (Table 2), depending on the inclusion or not of SEH within group 1 [21,29,40,49]. The recently described SET is most related to a putative exotoxin from an S. aureus isolate involved in bovine mastitis, and to streptococcal pyrogenic toxin type K (SpeK) [40]. TSST-1, which is functionally a superantigen with no emetic activity, is more distant to SEs and SEls than to SSLs (staphylococcal superantigen-like proteins) [50]. The SSLs, first identified by screening staphylococcal genomes using two conserved amino acid motifs placed in the N-terminal and C-terminal domains of SAgs, are not mitogenic to T cells and do not bind MHC class II, although they display a wide array of activities targeting key elements of the innate and specific immunity, such as neutrophils, complement factor C5, and IgA [51,52,53,54,55,56].

The three-dimensional structures of TSST-1 [57,58] and several SEs and SEls [59,60,61,62,63,64,65,66,67,68,69] have been solved by crystallography (Table 1). The structures are remarkably conserved, although they interact differently with MHC class II molecules, and show different TCR specificity [70]. They are compact ellipsoidal proteins with two unequal domains separated by a shallow grove. The larger C-terminal domain is a β-grasp fold consisting of four- to five-strand β-sheet that packs against a highly conserved α-helix [71]. The smaller N-terminal domain consists of a mixed β-barrel with Greek-key topology, similar to the OB (oligosaccharide/oligonucleotide binding)-fold [72] also found in many other bacterial toxins (SSLs, streptococcal superantigens, nucleases and toxins of the AB5 family, including cholera and pertussis toxins, and verotoxin) [29,50]. The two domains are stabilized by close packing and by a section of the N-terminus that extends over the top of the C-terminal domain. The N-terminal extension contributes substantially to the TCR-binding site, located in the cleft between the two protein domains, while the MHC class II binding site is in the OB-fold [29,50]. The top of the N-terminal domain usually contains a highly flexible disulfide loop, which has been implicated with emetic activity (see below).

2.3. Mode of Action

Important efforts have been made to identify specific amino acids and domains within SEs which may be important for emesis, but results are still limited and controversial. Like TSST-1, SElL, and SElQ are nonemetic, while SEI displays weak emetic activity [38,41,42]. These toxins lack the disulfide loop characteristically found at the top of the N-terminal domain of other SEs. Nonetheless, the loop itself does not appear to be an absolute requirement for emesis, although it may stabilize a crucial conformation important for this activity [73]. Carboxymethylation of histidines on SEA or SEB generates proteins devoid of enterotoxicity, which still retain superantigenicity [75,76]. Analysis of the effects of carboxymethylation of each of the SEA histidines revealed that His61 is important for emesis, but not for T-cell proliferation [77]. Conversely, Leu48Gly and Phe44Ser mutant forms of SEA and SEB, respectively, do not bind MHC class II molecules or cause T-cell activation, but still provoke vomiting [78], hence separating emesis and superantigenicity as different functions of the proteins. Despite this, a high correlation exists between the two activities since, in most cases, genetic mutations resulting in a loss of superantigen activity also results in loss of emetic activity [78].

In contrast to the case of many other bacterial enterotoxins, specific cells and receptors in the digestive system have not been unequivocally linked to oral intoxication by a SE. It has been suggested that SEs stimulate the vagus nerve in the abdominal viscera, which transmits the signal to the vomiting center in the brain [79]. Supporting this idea, receptors on vagal afferent neurons are essential for SEA-triggered emesis [80], and capsaicin, a small molecular weight compound from chilli peppers that depletes peptidergic sensory nerve fibers, also diminishes SE effects in mammals [21]. In addition, SEs are able to penetrate the gut lining and activate local and systemic immune responses [81]. Release of inflammatory mediators (including histamine, leukotrienes, and neuroenteric peptide substance P) causes vomiting [82,83,84,85] and the emetic response can be eliminated by H2- and calcium channel-blockers, which also block the release of histamine [86]. Local immune system activation could also be responsible for the gastrointestinal damage associated with SE ingestion [87,88]. Inflammatory changes are observed in several regions of the gastrointestinal tract, but the most severe lesions appear in the stomach and the upper part of the small intestine [89]. The diarrhea sometimes associated with SEs intoxication may be due to the inhibition of water and electrolyte reabsorption in the small intestine [90,91]. In an attempt to link the two distinct activities of SEs, i.e., superantigenicity and enterotoxicity, it has been postulated that enterotoxin activity could facilitate transcitosis, enabling the toxin to enter the bloodstream and circulate through the body, thus allowing the interaction with antigen presenting- and T-cells that leads to superantigen activity [3,92]. In this way, circulation of SEs following ingestion of SEs as well as their spread from a S. aureus infection site, could have more profound effects upon the host versus if the toxin remains localized [21].

2.4. Enterotoxin Gene Location

All se and sel genes are located on accessory genetic elements, including plasmids, prophages, S. aureus pathogenicity islands (SaPIs), genomic island vSa, or next to the staphylococcal cassette chromosome (SCC) elements (Table 1). Most of these are mobile genetic elements, and their spread among S.aureus isolates can modify their ability to cause disease and contribute to the evolution of this important pathogen.

2.4.1. Plasmids

Plasmids have been long recognized as efficient vehicles for the spread of resistance and virulence determinants through horizontal gene transfer. In S. aureus, two kinds of plasmids carrying se/sel genes have been characterized (Table 1; Figure 1). Both contain sej and ser associated with either sed (pIB485-like) or with ses and set (pF5) [40,45,93].

The first plasmid described to carry an enterotoxin gene was pIB485, a 27.6 kilobase (kb) plasmid, in which first sed and latter selj were identified [45,94]. Enterotoxin SER was discovered by [93] in S. aureus strains associated with a food poisoning outbreak that occurred in Fukuoka City, Japan, in 1997, and the ser gene was shown to be located on a family of closely related plasmids, termed pF5 and pF5-like. These plasmids have similar restriction profiles and carry selj along with ser. More recently, two novel SE genes (ses and set) have also been detected on the Fukuoka plasmids [40,93]. Interestingly, the ser gene, together with sed and selj, has also been found in pIB485-like plasmids from laboratory strains, food poisoning outbreak isolates and healthy human isolates in Japan [93] and pIB485-like plasmids, varying in size and/or restriction profile were present in S. aureus isolates recovered in Spain from human nasal carriers and manually handled foods [95]. Two of them, named pUO-Sa-SED1 (~33 kb) and pUO-Sa-SED2 (~36 kb), carried sed, selj and ser, and have restriction patterns identical or similar to that of pIB485, while pUO-Sa-SED3 (53.5 kb; containing sed, selj and ser-like) has a different profile. A BLAST search ( of the sed, selj, ser, ses and set genes revealed additional pIB485-like and pF5-like plasmids obtained from human clinical isolates, whose sequences have been deposited in databases. At present, the evolutionary relationship between the two types of plasmids is unknown.

2.4.2. Prophages

Like most published S. aureus phages, those carrying se genes (sea, selk, selp and selq) belong to the Siphoviridae family. The temperate, tailed bacteriophages within this family have been classified according to three features [96]: (i) the lysogeny module, particularly the integrase that dictates the insertion site of the phage in the bacterial chromosome; (ii) the serogroup, based on differences in capsid, tail, and tail appendix proteins; and (iii) the holin gene of the lysis module. The Siphoviridae prophages carrying se genes belong to integrase group Sa3, serogroups Fa and Fb, and holin groups 255a and 255b. Three se/sel genes (sea, selk and selq) are present together in ФSa3ms and ФSa3mw, while a single se/sel gene (sea or selp) is carried by other prophages (Table 1; Figure 2).

Apart from enterotoxins, virulence factors involved in evasion of the innate immunity are also encoded on these phages. These include the chemotaxis inhibitory protein (CHIP, product of the chp gene) that binds to host chemokine receptors, particularly the C5a receptor and the formylated peptide receptor, preventing neutrophil chemotaxis and activation [97]; the staphylococcal complement inhibitor (SCIN, encoded by the scn gene) that interferes with all pathways of complement activation by blocking C3 convertases [98]; the staphylokinase (product of the sak gene) that leads to degradation of two major opsonins (IgG and C3b) through activation of surface-bound plasminogen into plasmin, and also inhibits the bactericidal effect of α-defensins [99,100]. The region encoding these virulence factors is known as the "innate inmune evasion cluster" [101] and is located at one or both ends of the phages. Integration of these phages into the S. aureus chromosome occurs by a site-specific recombination event between the attP site in the phage genome and the attB site located within the β-hemolysin gene in the bacterial chromosome [102]. While integration negatively converts β-hemolysin expression, it supplies other virulence genes.

2.4.3. Staphylococcus aureus Pathogenicity Islands

The SaPIs are mobile pathogenicity islands, which are widely distributed in S. aureus and have also been found in other species of Staphylococcus. SaPIs have a highly conserved overall organization, parallel to that of typical temperate bateriophages. Each one occupies a specific chromosomal site (attS), and always appears in the same orientation. From its integration site, the island can be induced to excise and replicate by one or more specific staphylococcal helper phages [103,104]. Following replication the SaPI DNA is efficiently encapsidated into infectious small-headed phage-like particles resulting in extremely high transfer frequencies.

SaPIs are very common in S. aureus (Table 1). They range in size from 15–17 kb, with the exceptions of SaPIbov2 (27 kb) and a highly degenerated SaPI (3.14 kb) present in some sequenced genomes. The complete nucleotide sequence is known for 20 SaPIs, and some of them carry genes encoding TSST-1 and/or one or more SEs (Figure 3). For instance, tst is found together with selk and selq in SaPI1, with sec3 and sell in SaPIm1 and SaPIn1, and with sell and sec in SaPIbov1; seb, selq and selk have been reported in SaPI3; selk and selq in SaPI5; and sec4 and sell2 in SaPImw2 [105]. Induction of a SaPI is likely to originate an increase in the copy number of the toxin genes, and therefore to an increase in toxin production, as described for lysogenic phages [106].

2.4.4. vSa Genomic Islands

The term vSa refers to non-phage and non-SCC genomic islands that are exclusively present in S. aureus, often (but not always) encode virulence determinants, are inserted at specific loci in the chromosome and are associated with either intact or remnant DNA recombinases [107,108]. Two major vSa genomic islands, namely vSaα and vSaβ, each of about 20–30 kb, are present in all S. aureus genomes sequenced so far, but absent in other Staphylococcus species, including S. epidermidis. Though vSaα and vSaβ could have been acquired by horizontal gene transfer, actually there is not evidence that they can move. Each of these islands carries two copies of the genes encoding the recognition (hsdS) and methylation (hsdM) subunits of the Sau1 type I restriction-modification system. A single copy of the gene for the restriction subunit is located elsewhere in the S. aureus chromosome [109]. The hsdS genes of the Sau1 system diverge significantly between members of different lineages and this determines variations in the sequences that will be specifically recognized as targets for modification through methylation. Since only modified sequences will be protected against restriction, exchange of DNA between members of same lineage will be allowed, while DNA transferred between isolates of different lineages will be digested. Because of this, the Sau1 system has been considered as a key factor in the control of lineage evolution.

Both vSaα and vSaβ contain clusters of genes encoding known or putative virulence factors. vSaα carries a cluster of lipoprotein-encoding genes (lpl cluster), and the set (staphylococcal exotoxin-like) cluster [55,110], later re-named as the ssl (staphylococcal superantigen-like) cluster [30]. The ssl cluster consists of a series of related genes (between 7 and 11) coding for proteins that share a common architecture with SAgs but do not function as such [50]. However, they have alternative effects on the host immune system, acting on IgA, complement factor C5 (as demonstrated for SSL7; [53]), or neutrophils (SSL5 [111] and SSL11 [52]). vSaβ carries a serine protease gene (spl) cluster, genes for the components of the LukED leukocidin (lukD and lukE), genes for lantibiotic biosynthesis (bsa) and/or the enterotoxin gene cluster (egc), which includes a variable number of se/sel genes forming an operon [36]. Two representative types of vSaβ, the genomic island carrying se genes, are showed in Figure 4.

It has been suggested that the egc cluster arose from an ancestral se gene, through tandem duplication and further variation, while gene recombination has created variant toxins with different biological activities [28,36,112]. The dynamic evolution of this cluster that has been considered as a nursery of se/sel genes [36] is reflected in the number of variants already known (Figure 5).

The first egc (egc1) was discovered in 2001 and consists of two SE genes (seg and sei), three SEl genes (selm, seln and selo), and two pseudogenes (φent1 and φent2) [36,113]. Afterward, a second egc variant (egc2) containing an additional SEl gene (selu) was described [37]. The latter gene has been generated by fusion of the two egc1 pseudogenes, due to a 15 nucleotide insertion in φent1 and a single adenine deletion that abolishes a stop codon within the same gene. In addition, allelic variants of each of the egc2 genes compose the egc3 cluster [37,114,115], and a new selu variant (selu2) and a novel sel gene (selv) are present in egc4 [28]. A recombination event between selm and sei produced selv, while deletion of one adenine between the overlapping 5’ and 3’ ends of the φent2 and φent1 pseudogenes generated selu2 (which was proposed to be renamed as selw) [116]. Incomplete egc clusters, lacking one or more genes of the classical egc1, as well as variants carrying insertion sequences within seln, seg or sei, have also been described [28,117]. These structures have been considered as evolutionary intermediates of the egc cluster [28]. Moreover, the fact that each of the three major homology groups of SEs/SEs (Table 2) contains enterotoxins encoded by genes of the egc operon led to the proposal that all se/sels originated from the egc cluster [29].

2.4.5. Enterotoxin Genes in the Proximity of the Staphylococcal Cassette Chromosome

The seh gene, flanked by a truncated selo gene and a putative transposase gene, have been found in close proximity of the non-mecA containing SCC element harbored by MSSA (methicillin susceptible S. aureus) strain 476; the SCCmec type IV of S. aureus MW2; and the SCCmec type IV of a collection of highly related community-associated S. aureus ([118]; Figure 6). In the latter strains, acquisition of the seh element could have stabilized the integration of SCCmec type IV, which is unable to excise [118].

2.5. Staphylococcal Enterotoxins and Food Poisoning Outbreaks

Independently of their origin, enterotoxigenic S. aureus often differ in the number of mobile genetic elements and se/sel genes therein, as well as in the enterotoxins they produce. SEA, either alone or together with other SEs/SEls, is the enterotoxin most commonly reported in foods, and is also considered as the main cause of SFP, probably due to its extraordinarily high resistance to proteolytic enzymes [3,119,120]. The predominance of SEA is well documented in different countries. As relevant examples: (i) a comprehensive study of 359 outbreaks that occurred in the United Kingdom (UK) between 1969 and 1990 revealed that 79% of the S. aureus strains produced SEA [121]. Meat, poultry and their products, particularly ham and chicken, were the vehicle in 75% of the incidents. SEA was detected alone in 56.9% of the outbreaks and, in conjunction with SED, SEB, SEC or SEB and SED in a lower number of outbreaks (15.4, 3.4, 2.5 or 1.1%, respectively); (ii) SEA was also the enterotoxin most frequently found among 31 SFP outbreaks in France (69.7%), which were associated with a great variety of foods including milk products, different types of meat, and salads, between 1981 and 2002 [122]. In agreement with this, sea was the most common gene in the isolates tested, followed by sed, seg, sei and she; (iii) In Austria, an SFP outbreak that affected 40 children in 2007 was attributed to S. aureus isolates producing SEA and SED. Bovine milk products were identified as the source of the outbreak, and the cows, not the dairy owner, were the more likely reservoir of the SEs-producing S. aureus [123]; (iv) SEA was also the most common enterotoxin recovered from food poisoning outbreaks in USA (77.8% of all outbreaks) followed by SED and SEB [124]; (v) A study of S. aureus obtained from dairy products, responsible for 16 outbreaks in Brazil revealed that the most frequently encountered enterotoxin gene was sea followed by seb [125]. Finally, (vi) several studies have investigated the distribution of SEs and se/sel genes in S. aureus from foods and SFP outbreaks in Asian countries. Among strains recovered from patients associated with SFP outbreaks during 2001-2003 in Taiwan, sea was the most common gene, followed by seb and sec [13]. In Korea, about 90% of food poisoning isolates were reported to contain the sea gene [126]. SEA also was the most common SE associated to SFP in Japan [127]. In this country, an extensive outbreak that occurred in 2000 was attributed to low-fat milk containing SEA [128], while a recent outbreak (2009) was due to crepes containing SEA and SEC [129].

SEB, SEC or SED alone have been also implicated in SFP outbreaks through the world [121,122,125]. Interestingly, an outbreak, which affected three members of the same family in USA, was caused by coleslaw-containing SEC produced by a community-acquired methicillin resistant S. aureus from an asymptomatic food handler [130]. The fifth classical enterotoxin, SEE, has been infrequently reported in foods and food-producing animals, and its involvement in SFP outbreaks has only been demonstrated in rare occasions. However, six SFP outbreaks, which occurred in France at the end of 2009, were caused by SEE present in soft cheese made from unpasteurized milk. This enterotoxin has also been associated with outbreaks in USA and UK [33,121,131,132,133].

In contrast to classical SEs, the relationship between the novel SEs/SEls and SFP is not fully understood. Among them, SEG, SEH and SEI, SER, SES, and SET have shown to be emetic after oral administration in a primate model, while the emetic activity of SElL and SElP has only been demonstrated in rabbits and the small insectivore Suncus murinus, respectively [39,43]. The remaining SEls either lack emetic properties (SElQ), or have not been tested (SElJ, SElK, SElM, SElN, SElO, SElU, SElU2 and SElV). Moreover, commercial kits are not available for immunological detection of these SEs and SEls, although ELISA (enzyme-linked immunosorbent assay) has been described for SEH [134] and for SEG and SEI [135]. Of the new enterotoxins, only SEH-producing strains have clearly been involved in SFP outbreaks [134,136,137,138], but results from different researchers have shown the high incidence of genes encoding new SEs and SEls among food-borne S. aureus [131,139,140,141]. Mc Lauchlin et al. [131] revealed that 23 staphylococcal strains implicated in SFP outbreaks in UK, in which classical se genes were not detected, harbored one or more of the new se/sel genes, i.e., seg, seh, sei or selj. It is possible that the corresponding SEs might have been the cause of these outbreaks. The presence of egc genes was also shown in food-associated S. aureus from other countries [131,140,141,142,143,144], and newly described SE or SEl genes, particularly those belonging to the egc cluster, were more frequently detected in S. aureus strains isolated from raw pork and chicken meat in Korea than genes encoding classical SEs [145]. Despite this, egc-encoded SEs or SEls have not yet been directly implied in typical cases of SFP, although SEG and SEI have been reported as the cause of chronic diarrhea associated with severe but reversible enteropathy in two malnourished neonates [146].

3. Conclusions

SEs and SEls produced by S. aureus belong to the fascinating family of superantigens, which sabotage the immune system of the host by targeting the innate and adaptive responses. Members of the family are well characterized with regard to superantigenic activity. However, the bases for the enterotoxigenic activity associated with a number of S. aureus superantigens remain elusive. Likewise, a direct relationship of S. aureus SEs (with demonstrated emetic activity) and SEls (which lack emetic activity or have yet to be tested) with pathogenicity has not always been established, and the reasons for the redundancy of se/sel genes within the same bacterium deserve further attention. Of particular interest is the egc cluster, regarded as a nursery of se/sel genes in continuing evolution. The cluster and its multiple variants, located on the νSaβ genomic island, are widely distributed in S. aureus of any origin, and results from our group indicate that they are the most common superantigenes in S. aureus recovered from clinical samples, healthy carriers, cows with subclinical mastitis and foods [143,147,148,149]. However, a direct involvement of egc-encoded SEs in food poisoning has not been demonstrated, and attempts to elucidate their pathogenic role are still scarce [146,150,151,152]. In summary, although a wealth of information on SEs and SEls is already available, they still represent an active field of research, which will certainly provide new exciting findings in forthcoming years.


Experience in the subject derives from research supported by projects FISS PI052489 and FISS PI080656 from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). M. A. Argudín was supported by grant FPU AP-2004-3641 from the Ministry of Science and Innovation, Spain, co-funded by the European Social Fund.

1.. Dinges M.M.,Orwin P.M.,Schlievert P.M.. Exotoxins of Staphylococcus aureusClin. Microbiol. Rev.Year: 200013163410627489
2.. Le Loir Y.,Baron F.,Gautier M.. Staphylococcus aureus and food poisoningGenet. Mol. Res.Year: 20032637612917803
3.. Balaban N.,Rasooly A.. Staphylococcal enterotoxinsInt. J. Food Microbiol.Year: 20006111011028954
4.. Murray R.J.. Recognition and management of Staphylococcus aureus toxin-mediated diseaseIntern. Med. J.Year: 20052S106S11916271055
5.. Tranter H.S.. Foodborne staphylococcal illnessLancetYear: 1990336104410461977028
6.. Kluytmans J.A.J.W.,Wertheim H.F.L.. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infectionsInfectionYear: 2005333815750752
7.. Stewart G.C.. Staphylococcus aureusFoodborne pathogens: Microbiology and Molecular BiologyFratamico P.M.,Bhunia A.K.,Smith J.L.Caister Academic PressNorfolk, UKYear: 2005273284
8.. Tamarapu S.,McKillip J.L.,Drake M.. Development of a multiplex polymerase chain reaction assay for detection and differentiation of Staphylococcus aureus in dairy productsJ. Food Prot.Year: 20016466466811347997
9.. Wieneke A.A.,Roberts D.,Gilbert R.J.. Staphylococcal food poisoning in the United Kingdom, 1969–1990Epidemiol. Infect.Year: 19931105195318519317
10.. Qi Y.,Miller K.J.. Effect of low water activity on staphylococcal enterotoxin A and B biosynthesisJ. Food Prot.Year: 20006347347810772212
11.. Scott W.J.. Water relations of Staphylococcus aureus at 30 degrees CAust. J. Biol. Sci.Year: 1953654956413126033
12.. The community summary report on trends and sources of zoonoses, zoonotic agents, antimicrobial resistance and foodborne outbreaks in the European Union in 2006EFSA J.Year: 20071301310
13.. Chiang Y.C.,Liao W.W.,Fan C.M.,Pai W.Y.,Chiou C.S.,Tsen H.Y.. PCR detection of staphylococcal enterotoxins (SEs) N, O, P, Q, R, U, and survey of SE types in Staphylococcus aureus isolates from food-poisoning cases in TaiwanInt. J. Food Microbiol.Year: 2008121667318068843
14.. Delmas G.,Le Querrec F.,Weill F.-X.,Gallay A.,Espié E.,Haeghebaert S.,Vaillant V. . Les toxi-infections alimentairesSurveillance nationale des maladies infectieuses 2001–2003Institut de Veille SanitaireSaint-Maurice, FranceYear: 2005110
15.. Mead P.S.,Slutsker L.,Dietz V.,McCaig L.F.,Bresee J.S.,Shapiro C.,Griffin P.M.,Tauxe R.V.. Food-related illness and death in the United StatesEmerg. Infect. Dis.Year: 1999560762510511517
16.. Betley M.J.,Borst D.W.,Regassa L.B.. Staphylococcal enterotoxins, toxic shock syndrome toxin and streptococcal pyrogenic exotoxins: a comparative study of their molecular biologyChem. Immunol.Year: 1992551351418613
17.. Bergdoll M.S.. Staphylococcal intoxicationsFoodborne Infections and IntoxicationsReimann H.,Bryan F.L.Academic Press IncNew York, NY, USAYear: 1979443494
18.. Czop J.K.,Bergdoll M.S.. Staphylococcal enterotoxin synthesis during the exponential, transitional, and stationary growth phasesInfect. Inmun.Year: 19749229235
19.. Derzelle S.,Dilasser F.,Duquenne M.,Deperrois V.. Differential temporal expression of the staphylococcal enterotoxins genes during cell growthFood Microbiol.Year: 20092689690419835778
20.. Otero A.,García M.L.,García M.C.,Moreno B.,Bergdoll M.S.. Production of staphylococcal enterotoxins C1 and C2 and thermonuclease throughout the growth cycleAppl. Environ. Microbiol.Year: 1990565555592306093
21.. Larkin E.A.,Carman R.J.,Krakauer T.,Stiles B.G.. Staphylococcus aureus: the toxic presence of a pathogen extraordinaireCurr. Med. Chem.Year: 2009164003401919747126
22.. Bergdoll M.S.. EnterotoxinsStaphylococci and Staphylococcal InfectionsEasman C.S.F.,Adlam C.Academic Press IncLondon, UKYear: 19832559598
23.. Evenson M.L.,Hinds M.W.,Bernstein R.S.,Bergdoll M.S.. Estimation of human dose of staphylococcal enterotoxin A from a large outbreak of staphylococcal food poisoning involving chocolate milkInt. J. Food. Microbiol.Year: 198873113163275329
24.. Schantz E.J.,Roessler W.G.,Wagman J.,Spero L.,Dunnery D.A.,Bergdoll M.S.. Purification of staphylococcal enterotoxin BBiochemistryYear: 19654101110164953912
25.. Fleischer B.,Mittrücker H.W.,Metzroth B.,Braun M.,Hartwig U.. Mitogenic toxins as MHC class II-dependent probes for T cell antigen receptorsBehring Inst. Mitt.Year: 1991881701762049035
26.. Marrack P.,Kappler J.. The staphylococcal enterotoxins and their relativesScienceYear: 1990248106610682343314
27.. Petersson K.,Pettersson H.,Skartved N.J.,Walse B.,Forsberg G.. Staphylococcal enterotoxin H induces V alpha-specific expansion of T cellsJ. Immunol.Year: 20031704148415412682246
28.. Thomas D.Y.,Jarraud S.,Lemercier B.,Cozon G.,Echasserieau K.,Etienne J.,Gougeon M.L.,Lina G.,Vandenesch F.. Staphylocccal enterotoxin-like toxins U2 and V, two new staphylococcal superantigens arising from recombination within the enterotoxin gene clusterInfect. Immun.Year: 2006744724473416861660
29.. Thomas D.,Chou S.,Dauwalder O.,Lina G.. Diversity in Staphylococcus aureus enterotoxinsChem. Immunol. AllergyYear: 200793244117369698
30.. Lina G.,Bohach G.A.,Nair S.P.,Hiramatsu K.,Jouvin-Marche E.,Mariuzza R.. Standard nomenclature for the superantigens expressed by StaphylococcusJ. Infect. Dis.Year: 20041892334233615181583
31.. Bergdoll M.S.,Surgalla M.J.,Dack G.M.. Staphylococcal enterotoxin: Identification of a specific precipitating antibody with enterotoxin neutralizing propertyJ. Immunol.Year: 19598333433813799262
32.. Bergdoll M.S.,Borja C.R.,Avena R.M.. Identification of a new enterotoxin as enterotoxin CJ. Bacteriol.Year: 196590148114854954560
33.. Bergdoll M.S.,Borja C.R.,Robbins R.N.,Weiss K.F.. Identification of enterotoxin EInfect. Immun.Year: 197145935955005309
34.. Casman E.P.. Further serological studies of staphylococcal enterotoxinJ. Bacteriol.Year: 19607984985613808165
35.. Casman E.P.,Bennett R.W.,Dorsey A.E.,Issa J.A.. Identification of a fourth staphylococcal enterotoxin, enterotoxin DJ. Bacteriol.Year: 196794187518824965366
36.. Jarraud S.,Peyrat M.A.,Lim A.,Tristan A.,Bes M.,Mougel C.,Etienne J.,Vandenesch F.,Bonneville M.,Lina G.. egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureusJ. Immunol.Year: 200116666967711123352
37.. Letertre C.,Perelle S.,Dilasser F.,Fach P. . Identification of a new putative enterotoxin SEU encoded by the egc cluster of Staphylococcus aureusJ. Appl. Microbiol.Year: 20039538431280745210.1046/j.1365-2672.2003.01957.x
38.. Munson S.H.,Tremaine M.T.,Betley M.J.,Welch R.A.. Identification and characterization of staphylococcal enterotoxin types G and I from Staphylococcus aureusInfect Immun.Year: 199866333733489632603
39.. Omoe K.,Imanishi K.,Hu D.L.,Kato H.,Fugane Y.,Abe Y.,Hamaoka S.,Watanabe Y.,Nakane A.,Uchiyama T.,Shinagawa K.. Characterization of novel staphylococcal enterotoxin-like toxin type PInfect. Immun.Year: 2005735540554616113270
40.. Ono H.K.,Omoe K.,Imanishi K.,Iwakabe Y.,Hu D.L.,Kato H.,Saito N.,Nakane A.,Uchiyama T.,Shinagawa K.. Identification and characterization of two novel staphylococcal enterotoxins, types S and TInfect. Immun.Year: 2008764999500518710864
41.. Orwin P.M.,Leung D.Y.,Donahue H.L.,Novick R.P.,Schlievert P.M.. Biochemical and biological properties of staphylococcal enterotoxin KInfect. Immun.Year: 20016936036611119525
42.. Orwin P.M.,Leung D.Y.,Tripp T.J.,Bohach G.A.,Earhart C.A.,Ohlendorf D.H.,Schlievert P.M.. Characterization of a novel staphylococcal enterotoxin-like superantigen, a member of the group V subfamily of pyrogenic toxinsBiochemistryYear: 200241140331404012437361
43.. Orwin P.M.,Fitzgerald J.R.,Leung D.Y.,Gutierrez J.A.,Bohach G.A.,Schlievert P.M.. Characterization of Staphylococcus aureus enterotoxin LInfect. Immun.Year: 2003712916291912704169
44.. Su Y.C.,Wong A.C.. Identification and purification of a new staphylococcal enterotoxin, HAppl. Environ. Microbiol.Year: 199561143814437747964
45.. Zhang S.,Iandolo J.J.,Stewart G.C.. The enterotoxin D plasmid of Staphylococcus aureus encodes a second enterotoxin determinant (sej)FEMS Microbiol. Lett.Year: 19981682272339835033
46.. Bergdoll M.S.,Crass B.A.,Reiser R.F.,Robbins R.N.,Davis J.P.. A new staphylococcal enterotoxin, enterotoxin F, associated with toxic-shock-syndrome Staphylococcus aureus isolatesLancetYear: 19815101710216112412
47.. Reiser R.F.,Robbins R.N.,Khoe G.P.,Bergdoll M.S.. Purification and some physicochemical properties of toxic-shock toxinBiochemistryYear: 198322390739126615808
48.. Couch J.L.,Soltis M.T.,Betley M.J.. Cloning and nucleotide sequence of the type E staphylococcal enterotoxin geneJ. Bacteriol.Year: 1988170295429603384800
49.. Uchiyama T.,Imanishi K.,Miyoshi-Akiyama T.,Kato H.. Staphylococcal superantigens and the diseases they causeThe Comprehensive Sourcebook of Bacterial Protein Toxins3rdAlouf J.E.,Popoff M.R.Academic PressBurlington, VT, USAYear: 2006830843
50.. Fraser J.D.,Proft T.. The bacterial superantigen and superantigen-like proteinsImmunol. Rev.Year: 200822522624318837785
51.. Baker H.M.,Basu I.,Chung M.C.,Caradoc-Davies T.,Fraser J.D.,Baker E.N.. Crystal structures of the staphylococcal toxin SSL5 in complex with sialyl Lewis X reveal a conserved binding site that shares common features with viral and bacterial sialic acid binding proteinsJ. Mol. Biol.Year: 20073741298130817996251
52.. Chung M.C.,Wines B.D.,Baker H.,Langley R.J.,Baker E.N.,Fraser J.D.. The crystal structure of staphylococcal superantigen-like protein 11 in complex with sialyl Lewis X reveals the mechanism for cell binding and immune inhibitionMol. Microbiol.Year: 2007661342135518045383
53.. Langley R.,Wines B.,Willoughby N.,Basu I.,Proft T.,Fraser J.D.. The staphylococcal superantigen-like protein 7 binds IgA and complement C5 and inhibits IgA-Fc alpha RI binding and serum killing of bacteriaJ. Immunol.Year: 20051742926293315728504
54.. Ramsland P.A.,Willoughby N.,Trist H.M.,Farrugia W.,Hogarth P.M.,Fraser J.D.,Wines B.D.. Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1Proc. Natl. Acad. Sci. USAYear: 2007104150511505617848512
55.. Williams R.J.,Ward J.M.,Henderson B.,Poole S.,O'Hara B.P.,Wilson M.,Nair S.P.. Identification of a novel gene cluster encoding staphylococcal exotoxin-like proteins: Characterization of the prototypic gene and its protein product, SET1Infect. Immun.Year: 2000684407441510899837
56.. Wines B.D.,Willoughby N.,Fraser J.D.,Hogarth P.M.. A competitive mechanism for staphylococcal toxin SSL7 inhibiting the leukocyte IgA receptor, Fc alphaRI, is revealed by SSL7 binding at the C alpha2/C alpha3 interface of IgAJ. Biol. Chem.Year: 20062811389139316293625
57.. Acharya K.R.,Passalacquam E.F.,Jones E.Y.,Harlos K.,Stuart D.I.,Brehm R.D.,Tranter H.S.. Structural basis of superantigen action inferred from crystal structure of toxic-shock syndrome toxin-1NatureYear: 199436794978107781
58.. Prasad G.S.,Earhart C.A.,Murray D.L.,Novick R.P.,Schlievert P.M.,Ohlendorf D.H.. Structure of toxic shock syndrome toxin 1BiochemistryYear: 19933213761137668268150
59.. Fernández M.M.,Bhattacharya S.,De Marzi M.C.,Brown P.H.,Kerzic M.,Schuck P.,Mariuzza R.A.,Malchiodi E.L.. Superantigen natural affinity maturation revealed by the crystal structure of staphylococcal enterotoxin G and its binding to T-cell receptor Vbeta8.2ProteinsYear: 2007683894021742725010.1002/prot.21388
60.. Günther S.,Varma A.K.,Moza B.,Kasper K.J.,Wyatt A.W.,Zhu P.,Rahman A.K.,Li Y.,Mariuzza R.A.,McCormick J.K.,Sundberg E.J.. A novel loop domain in superantigens extends their T cell receptor recognition siteJ. Mol. Biol.Year: 200737121022117560605
61.. Håkansson M.,Petersson K.,Nilsson H.,Forsberg G.,Björk P.,Antonsson P.,Svensson L.A.. The crystal structure of staphylococcal enterotoxin H: implication for binding properties to MHC class II and TcR moleculesJ. Mol. Biol.Year: 200030252753710986116
62.. Papageorgiou A.C.,Acharya K.R.,Shapiro R.,Passalacqua E.F.,Brehm R.D.,Tranter H.S. Crystal structure of the superantigen enterotoxin C2 from Staphylococcus aureus reveals a zinc-binding siteStructureYear: 19953769779758289410.1016/S0969-2126(01)00212-X
63.. Papageorgiou A.C.,Tranter H.S.,Acharya K.R.. Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: Implications for superantigen recognition by MHC class II molecules and T-cell receptorsJ. Mol. Biol.Year: 19982776179951473910.1006/jmbi.1997.1577
64.. Schad E.M.,Zaitseva I.,Zaitsev V.N.,Dohlsten M.,Kalland T.,Schlievert P.M.,Ohlendorf D.H.,Svensson L.A.. Crystal structure of the superantigen staphylococcal enterotoxin type AEMBO J.Year: 199514329233017628431
65.. Singh B.R.,Fu F.N.,Ledoux D.N.. Crystal and solution structures of superantigenic staphylococcal enterotoxins comparedNat. Struct. Biol.Year: 199413583607664046
66.. Sundström M.,Hallén D.,Svensson A.,Schad E.,Dohlsten M.,Abrahmsén L.. The Co-crystal structure of staphylococcal enterotoxin type A with Zn2+ at 2.7 A resolution. Implications for major histocompatibility complex class II bindingJ. Biol. Chem.Year: 199627132212322168943278
67.. Sundström M.,Abrahmsén L.,Antonsson P.,Mehindate K.,Mourad W.,Dohlsten M.. The crystal structure of staphylococcal enterotoxin D type D reveals Zn2+ mediated homodimersationEMBO J.Year: 199615683268409003758
68.. Swaminathan S.,Furey W.,Pletcher J.,Sax M.. Crystal structure of staphylococcal enterotoxin B, a superantigenNatureYear: 19923598018061436058
69.. Swaminathan S.,Furey W.,Pletcher J.,Sax M.. Residues defining V beta specificity in staphylococcal enterotoxinsNat. Struct. Biol.Year: 199586806867552730
70.. McCormick J.K.,Yarwood J.M.,Schlievert P.M.. Toxic shock syndrome and bacterial superantigens: An updateAnnu. Rev. Microbiol.Year: 2001557710411544350
71.. Mitchell D.T.,Levitt D.G.,Schlievert P.M.,Ohlendorf D.H.. Structural evidence for the evolution of pyrogenic toxin superantigensJ. Mol. Evol.Year: 20005152053111116326
72.. Murzin A.G.. OB(oligonucleotide/oligosaccharide binding)-fold: Common structural and functional solution for non-homologous sequencesEMBO J.Year: 1993128618678458342
73.. Hovde C.J.,Marr J.C.,Hoffmann M.L.,Hackett S.P.,Chi Y.I.,Crum K.K.,Stevens D.L.,Stauffacher C.V.,Bohach G.A.. Investigation of the role of the disulphide bond in the activity and structure of staphylococcal enterotoxin C1Mol. Microbiol.Year: 1994138979097815947
74.. Wang X.,Xu M.,Cai Y.,Yang H.,Zhang H.,Zhang C.. Functional analysis of the disulphide loop mutant of staphylococcal enterotoxin C2Appl. Microbiol. Biotechnol.Year: 20098286187119082587
75.. Alber G.,Hammer D.K.,Fleischer B.. Relationship between enterotoxic- and T lymphocyte-stimulating activity of staphylococcal enterotoxin BJ. Immunol.Year: 1990144450145062161873
76.. Stelma G.N.,Bergdoll M.S.. Inactivation of staphylococcal enterotoxin A by chemical modificationBiochem. Biophys. Res. Commun.Year: 19821051211266807298
77.. Hoffman M.,Tremaine M.,Mansfield J.,Betley M.. Biochemical and mutational analysis of the histidine residues of staphylococcal enterotoxin AInfect. Immun.Year: 1996648858908641796
78.. Harris T.O.,Grossman D.,Kappler J.W.,Marrack P.,Rich R.R.,Betley M.J.. Lack of complete correlation between emetic and T-cell-stimulatory activities of staphylococcal enterotoxinsInfect. Immunol.Year: 199361317531838335347
79.. Sugiyama H.,Hayama T.. Abdominal viscera as site of emetic action for staphylococcal enterotoxin in monkeyJ. Infect. Dis.Year: 19651153303364953783
80.. Hu D.L.,Zhu G.,Mori F.,Omoe K.,Okada M.,Wakabayashi K.,Kaneko S.,Shinagawa K.,Nakane A.. Staphylococcal enterotoxin induces emesis through increasing serotonin release in intestine and it is downregulated by cannabinoid receptor 1Cell. Microbiol.Year: 200792267227717517065
81.. Shupp J.W.,Jett M.,Pontzer C.H.. Identification of a transcytosis epitope on staphylococcal enterotoxinsInfect. Immun.Year: 2002702178218611895985
82.. Alber G.,Scheuber P.H.,Reck B.,Sailer-Kramer B.,Hartmann A.,Hammer D.K.. Role of substance P in immediate-type skin reactions induced by staphylococcal enterotoxin B in unsensitized monkeysJ. Allergy Clin. Immunol.Year: 198968808852480969
83.. Jett M.,Brinkley W.,Neill R.,Gemski P.,Hunt R.. Staphylococcus aureus enterotoxin B challenge of monkeys: Correlation of plasma levels of arachidonic acid cascade products with occurrence of illnessInfect. Immun.Year: 199058349434992172165
84.. Scheuber P.H.,Denzlinger C.,Wilker D.,Beck G.,Keppler D.,Hammer D.K.. Cysteinyl leukotrienes as mediators of staphylococcal enterotoxin B in the monkeyEur. J. Clin. Invest.Year: 1987174554592826171
85.. Shanahan F.,Denburg J.A.,Fox J.,Bienenstock J.,Befus D.. Mast cell heterogeneity: Effects of neuroenteric peptides on histamine releaseJ. Inmunol.Year: 1985135133113337
86.. Scheuber P.H.,Golecki J.R.,Kickhöfen B.,Scheel D.,Beck G.,Hammer D.K.. Skin reactivity of unsensitized monkeys upon challenge with staphylococcal enterotoxin B: A new approach for investigating the site of toxin actionInfect. Immun.Year: 1985508698762866161
87.. Holmberg S.D.,Blake P.A.. Staphylococcal food poisoning in the United States: New facts and old misconceptionsJAMAYear: 19842514874896690814
88.. Palmer E.D.. The morphologic consequences of acute exogenous (staphylococcic) gastroenteritis of the gastric mucosaGastroenterologyYear: 19511946247514887842
89.. Kent T.H.. Staphylococcal enterotoxin gastroenteritis in rhesus monkeysAm. J. Pathol.Year: 1966483874074955962
90.. Sheehan D.G.,Jervis H.R.,Takeuchi A.,Sprinz H.. The effect of staphylococcal enterotoxin on the epithelial mucosubstance of the small intestine of rhesus monkeysAm. J. Pathol.Year: 1970601184193441
91.. Sullivan R.. Effects of enterotoxin B on intestinal transport in vitroProc. Soc. Exp. Biol. Med.Year: 1969131115911625811968
92.. Hamad A.R.,Marrack P.,Kappler J.W.. Transcytosis of staphylococcal superantigen toxinsJ. Exp. Med.Year: 1997185144714549126925
93.. Omoe K.,Hu D.L.,Takahashi-Omoe H.,Nakane A.,Shinagawa K.. Identification and characterization of a new staphylococcal enterotoxin-related putative toxin encoded by two kinds of plasmidsInfect. Immun.Year: 2003716088609414500536
94.. Bayles K.W.,Iandolo J.J.. Genetic and molecular analyses of the gene encoding staphylococcal enterotoxin DJ. Bacteriol.Year: 1989171479948062549000
95.. Fueyo J.M.,Mendoza M.C.,Martín M.C.. Enterotoxins and toxic shock syndrome toxin in Staphylococcus aureus recovered from human nasal carriers and manually handled foods: Epidemiological and genetic findingsMicrobes Infect.Year: 2005718719415715991
96.. Goerke C.,Pantucek R.,Silva Holtfreter S.,Berit Schulte B.,Manuel Zink M.,Grumann D.,Bröker B.M.,Doskar J.,Wolz C.. Diversity of prophages in dominant Staphylococcus aureus clonal lineagesJ. Bacteriol.Year: 20091913462346819329640
97.. de Haas C.J.,Veldkamp K.E.,Peschel A.,Weerkamp F.,Van Wamel W.J.,Heezius E.C.,Poppelier M.J.,Van Kessel K.P.,van Strijp J.A.. Chemotaxis inhibitory protein of Staphylococcus aureus, a bacterial antiinflammatory agentJ. Exp. Med.Year: 200419968769514993252
98.. Rooijakkers S.H.,Ruyken M.,Roos A.,Daha M.R.,Presanis J.S.,Sim R.B.,van Wamel W.J.,van Kessel K.P.,van Strijp J.A.. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertasesNat. Immunol.Year: 2005692092716086019
99.. Ji Y.,Yin D.,Fox B.,Holmes D.J.,Payne D.,Rosenberg M.. Validation of antibacterial mechanism of action using regulated antisense RNA expression in Staphylococcus aureusFEMS Microbiol. Lett.Year: 200423117718414987762
100.. Rooijakkers S.H.,van Wamel W.J.,Ruyken M.,van Kessel K.P.,van Strijp J.A.. Anti-opsonic properties of staphylokinaseMicrobes Infect.Year: 2005747648415792635
101.. van Wamel W.J.,Rooijakkers S.H.,Ruyken M.,van Kessel K.P.,van Strijp J.A.. The innate immune modulators staphylococcal complement inhibitor and chemotaxis inhibitory protein of Staphylococcus aureus are located on beta-hemolysin-converting bacteriophagesJ. Bacteriol.Year: 20061881310131516452413
102.. Coleman D.C.,Sullivan D.J.,Russell R.J.,Arbuthnott J.P.,Carey B.F.,Pomeroy H.M.. Staphylococcus aureus bacteriophages mediating the simultaneous lysogenic conversion of beta-lysin, staphylokinase and enterotoxin A: Molecular mechanism of triple conversionJ. Gen. Microbiol.Year: 1989135167916972533245
103.. Lindsay J.A.,Ruzin A.,Ross H.F.,Kurepina N.,Novick R.P.. The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureusMol. Microbiol.Year: 1998295275439720870
104.. Tallent S.M.,Langston T.B.,Moran R.G.,Christie G.E.. Transducing particles of Staphylococcus aureus pathogenicity island SaPI1 are comprised of helper phage-encoded proteinsJ. Bacteriol.Year: 20071897520752417693489
105.. Novick R.P.,Subedi A.. The SaPIs: mobile pathogenicity islands of StaphylococcusChem. Immunol. AllergyYear: 200793425717369699
106.. Sumby P.,Waldor M.K.. Transcription of the toxin genes present within the Staphylococcal phage phiSa3ms is intimately linked with the phage's life cycleJ. Bacteriol.Year: 20031856841685114617648
107.. Baba T.,Takeuchi F.,Kuroda M.,Yuzawa H.,Aoki K.,Oguchi A.,Nagai Y.,Iwama N.,Asano K.,Naimi T.,Kuroda H.,Cui L.,Yamamoto K.,Hiramatsu K.. Genome and virulence determinants of high virulence community-acquired MRSALancetYear: 20023591819182712044378
108.. Baba T.,Bae T.,Schneewind O.,Takeuchi F.,Hiramatsu K.. Genome sequence of Staphylococcus aureus strain Newman and comparative analysis of staphylococcal genomes: polymorphism and evolution of two major pathogenicity islandsJ. Bacteriol.Year: 20081903003101795138010.1128/JB.01000-07
109.. Waldron D.E.,Lindsay J.A.. Sau1: A novel lineage-specific type I restriction-modification system that blocks horizontal gene transfer into Staphylococcus aureus and between S. aureus isolates of different lineagesJ. Bacteriol.Year: 2006188557855851685524810.1128/JB.00418-06
110.. Fitzgerald J.R.,Reid S.D.,Ruotsalainen E.,Tripp T.J.,Liu M.,Cole R.,Kuusela P.,Schlievert P.M.,Järvinen A.,Musser J.M.. Genome diversification in Staphylococcus aureus: Molecular evolution of a highly variable chromosomal region encoding the staphylococcal exotoxin-like family of proteinsInfect. Immun.Year: 2003712827283812704157
111.. Bestebroer J.,Poppelier M.J.,Ulfman L.H.,Lenting P.J.,Denis C.V.,van Kessel K.P.,van Strijp J.A.,de Haas C.J.. Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rollingBloodYear: 20071092936294317132726
112.. Fitzgerald J.R.,Monday S.R.,Foster T.J.,Bohach G.A.,Hartigan P.J.,Meaney W.J.,Smith C.J.. Characterization of putative pathogenicity island from bovine Staphylococcus aureus encoding multiple superantigensJ. Bacteriol.Year: 2001183637011114901
113.. Monday S.R.,Bohach G.A.. Genes encoding staphylococcal enterotoxins G and I are linked and separated by DNA related to other staphylococcal enterotoxinsJ. Nat. ToxinsYear: 2001101811288724
114.. Collery M.M.,Smyth D.S.,Tumilty J.J.,Twohig J.M.,Smyth C.J.. Associations between enterotoxin gene cluster types egc1, egc2 and egc3, agr types, enterotoxin and enterotoxin-like gene profiles, and molecular typing characteristics of human nasal carriage and animal isolates of Staphylococcus aureusJ. Med. Microbiol.Year: 20095813251907464910.1099/jmm.0.005215-0
115.. Holden M.T.,Feil E.J.,Lindsay J.A.,Peacock S.J.,Day N.P.,Enright M.C.,Foster T.J.,Moore C.E.,Hurst L.,Atkin R.,Barron A.,Bason N.,Bentley S.D.,Chillingworth C.,Chillingworth T.,Churcher C.,Clark L.,Corton C.,Cronin A.,Doggett J.,Dowd L.,Feltwell T.,Hance Z.,Harris B.,Hauser H.,Holroyd S.,Jagels K.,James K.D.,Lennard N.,Line A.,Mayes R.,Moule S.,Mungall K.,Ormond D.,Quail M.A.,Rabbinowitsch E.,Rutherford K.,Sanders M.,Sharp S.,Simmonds M.,Stevens K.,Whitehead S.,Barrell B.G.,Spratt B.G.,Parkhill J.. Complete genomes of two clinical Staphylococcus aureus strains: Evidence for the rapid evolution of virulence and drug resistanceProc. Natl. Acad. Sci. USAYear: 20041019786979115213324
116.. Collery M.M.,Smyth C.J.. Rapid differentiation of Staphylococcus aureus isolates harbouring egc loci with pseudogenes psient1 and psient2 and the selu or seluv gene using PCR-RFLPJ. Med. Microbiol.Year: 20075620821617244802
117.. Omoe K.,Hu D.L.,Takahashi-Omoe H.,Nakane A.,Shinagawa K.. Comprehensive analysis of classical and newly described staphylococcal superantigenic toxin genes in Staphylococcus aureus isolatesFEMS Microbiol. Lett.Year: 200524619119815899405
118.. Noto M.J.,Archer G.L.. A subset of Staphylococcus aureus strains harboring staphylococcal cassette chromosome mec (SCCmec) type IV is deficient in CcrAB-mediated SCCmec excisionAntimicrob. Agents Chemother.Year: 2006502782278816870772
119.. Bergdoll M.S.. Monkey feeding test for staphylococcal enterotoxinMeth. Enzymol.Year: 19881653243333231111
120.. Holmberg S.D.,Blake P.A.. Staphylococcal food poisoning in the United States. New facts and old misconceptionsJAMAYear: 19842514874896690814
121.. Wieneke A.A.,Roberts D.,Gilbert R.J.. Staphylococcal food poisoning in the United Kingdom, 1969–90Epidemiol. Infect.Year: 19931105195318519317
122.. Kérouanton A.,Hennekinne J.A.,Letertre C.,Petit L.,Chesneau O.,Brisabois A.,De Buyser M.L.. Characterization of Staphylococcus aureus strains associated with food poisoning outbreaks in FranceInt. J. Food Microbiol.Year: 200711536937517306397
123.. Schmid D.,Fretz R.,Winter P.,Mann M.,Höger G.,Stöger A.,Ruppitsch W.,Ladstätter J.,Mayer N.,de Martin A.,Allerberger F.. Outbreak of staphylococcal food intoxication after consumption of pasteurized milk products, June 2007, AustriaWien. Klin. Wochenschr.Year: 200912112513119280138
124.. Casman E.P.. Staphylococal enterotoxinAnn. N.Y. Acad. Sci.Year: 19651281241314221871
125.. Veras J.F.,do Carmo L.S.,Tong L.C.,Shupp J.W.,Cummings C.,Dos Santos D.A.,Cerqueira M.M.,Cantini A.,Nicoli J.R.,Jett M.. A study of the enterotoxigenicity of coagulase-negative and coagulase-positive staphylococcal isolates from food poisoning outbreaks in Minas Gerais, BrazilInt. J. Infect. Dis.Year: 20081241041518206412
126.. Cha J.O.,Lee J.K.,Jung Y.H.,Yoo J.I.,Park Y.K.,Kim B.S.,Lee Y.S.. Molecular analysis of Staphylococcus aureus isolates associated with staphylococcal food poisoning in South KoreaJ. Appl. Microbiol.Year: 200610186487116968298
127.. Shimizu A.,Fujita M.,Igarashi H.,Takagi M.,Nagase N.,Sasaki A.,Kawano J.. Characterization of Staphylococcus aureus coagulase type VII isolates from staphylococcal food poisoning outbreaks (1980–1995) in Tokyo, Japan, by pulsed field gel electrophoresisJ. Clin. Microbiol.Year: 2000383746374911015395
128.. Asao T.,Kumeda Y.,Kawai T.,Shibata T.,Oda H.,Haruki K.,Nakazawa H.,Kozaki S.. 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 milkEpidemiol. Infect.Year: 2003130334012613743
129.. Kitamoto M.,Kito K.,Niimi Y.,Shoda S.,Takamura A.,Hiramatsu T.,Akashi T.,Yokoi Y.,Hirano H.,Hosokawa M.,Yamamoto A.,Agata N.,Hamajima N.. Food poisoning by Staphylococcus aureus at a university festivalJpn. J. Infect. Dis.Year: 20096224224319468193
130.. Jones T.F.,Kellum M.E.,Porter S.S.,Bell M.,Schaffner W.. An outbreak of community-acquired foodborne illness caused by methicillin-resistant Staphylococcus aureusEmerg. Infect. Dis.Year: 20028828411749755
131.. McLauchlin J.,Narayanan G.L.,Mithani V.,O’Neil G.. The detection of enterotoxins and toxic schock síndrome toxin genes in Staphylococcus aureus by polymerase chain reactionJ. Food Prot.Year: 20006347948810772213
132.. Morris C.A.,Conway H.D.,Everall P.H.. Food poisoning due to staphylococcal enterotoxin ELancetYear: 19722137513764118251
133.. Ostyn A.,De Buyser M.L.,Guillier F.,Groult J.,Felix B.,Salah S.,Delmas G.,Hennekinne J.A.. First evidence of a food poisoning outbreak due to staphylococcal enterotoxin type E, France, 2009Euro. Surveill.Year: 201015pii. 1952820394711
134.. Su Y.C.,Wong A.C.. Detection of staphylococcal enterotoxin H by an enzyme-linked immunosorbent assayJ. Food Prot.Year: 19965932733010463455
135.. Omoe K.,Ishikawa M.,Shimoda Y.,Hu D.L.,Ueda S.,Shinagawa K.. Detection of seg, seh, and sei genes in Staphylococcus aureus isolates and determination of the enterotoxin productivities of S. aureus isolates harboring seg, seh, or sei genesJ. Clin. Microbiol.Year: 2002408578621188040510.1128/JCM.40.3.857-862.2002
136.. Ikeda T.,Tamate N.,Yamaguchi K.,Makino S.. Mass outbreak of food poisoning disease caused by small amounts of staphylococcal enterotoxins A and HAppl. Environ. Microbiol.Year: 2005712793279515870376
137.. Jørgensen H.J.,Mathisen T.,Løvseth A.,Omoe K.,Qvale K.S.,Loncarevic S.. An outbreak of staphylococcal food poisoning caused by enterotoxin H in mashed potato made with raw milkFEMS Microbiol. Lett.Year: 200525226727216213675
138.. Pereira M.L.,do Carmo L.S.,dos Santos E.J.,Pereira J.L.,Bergdoll M.S.. Enterotoxin H in staphylococcal food poisoningJ. Food Prot.Year: 199659559561
139.. Abe J.,Ito Y.,Onimaru M.,Kohsaka T.,Takeda T.. Characterization and distribution of a new enterotoxin-related superantigen produced by Staphylococcus aureusMicrobiol. Immunol.Year: 200044798810803494
140.. Bania J.,Dabrowska A.,Bystron J.,Korzekwa K.,Chrzanowska J.,Molenda J.. Distribution of newly described enterotoxin-like genes in Staphylococcus aureus from foodInt. J. Food Microbiol.Year: 2006108364116380185
141.. Blaiotta G.,Ercolini D.,Pennacchia C.,Fusco V.,Casaburi A.,Pepe O.,Villani F.. PCR detection of staphylococcal enterotoxin genes in Staphylococcus spp. strains isolated from meat and dairy products. Evidence for new variants of seG and seI in S. aureus AB-8802J. Appl. Microbiol.Year: 2004977197301535772110.1111/j.1365-2672.2004.02349.x
142.. Jørgensen H.J.,Mørk T.,Caugant D.A.,Kearns A.,Rørvik L.M.. Genetic variation among Staphylococcus aureus strains from Norwegian bulk milkAppl. Environ. Microbiol.Year: 2005718352836116332822
143.. Martin M.C.,Fueyo J.M.,González-Hevia M.A.,Mendoza M.C.. Genetic procedures for identification of enterotoxigenic strains of Staphylococcus aureus from three food poisoning outbreaksInt. J. Food Microbiol.Year: 20049427928615246239
144.. Rosec J.P.,Gigaud O.. Staphylococcal enterotoxin genes of classical and new types detected by PCR in FranceInt. J. Food Microbiol.Year: 200277617012076039
145.. Hwang S.Y.,Kim S.H.,Jang E.J.,Kwon N.H.,Park Y.K.,Koo H.C.,Jung W.K.,Kim J.M.,Park Y.H.. Novel multiplex PCR for the detection of the Staphylococcus aureus superantigen and its application to raw meat isolates in KoreaInt. J. Food Microbiol.Year: 20071179910517439826
146.. Naik S.,Smith F.,Ho J.,Croft N.M.,Domizio P.,Price E.,Sanderson I.R.,Meadows N.J.. Staphylococcal enterotoxins G and I, a cause of severe but reversible neonatal enteropathyClin. Gastroenterol. Hepatol.Year: 2008625125418063418
147.. Argudín M.A.,Mendoza M.C.,Méndez F.J.,Martín M.C.,Guerra B.,Rodicio M.R.. Clonal complexes and diversity of exotoxin gene profiles in methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolates from patients in a Spanish hospitalJ. Clin. Microbiol.Year: 2009472097210519458176
148.. Fueyo J.M.,Mendoza M.C.,Alvarez M.A.,Martín M.C.. Relationships between toxin gene content and genetic background in nasal carried isolates of Staphylococcus aureus from Asturias, SpainFEMS Microbiol. Lett.Year: 200524344745415686848
149.. Fueyo J.M.,Mendoza M.C.,Rodicio M.R.,Muñiz J.,Alvarez M.A.,Martín M.C.. Cytotoxin and pyrogenic toxin superantigen gene profiles of Staphylococcus aureus associated with subclinical mastitis in dairy cows and relationships with macrorestriction genomic profilesJ. Clin. Microbiol.Year: 2005431278128415750096
150.. Dauwalder O.,Thomas D.,Ferry T.,Debard A.L.,Badiou C.,Vandenesch F.,Etienne J.,Lina G.,Monneret G.. Comparative inflammatory properties of staphylococcal superantigenic enterotoxins SEA and SEG: implications for septic shockJ. Leukoc. Biol.Year: 20068075375816885504
151.. Dauwalder O.,Pachot A.,Cazalis M.A.,Paye M.,Faudot C.,Badiou C.,Mougin B.,Vandenesch F.,Etienne J.,Lina G.,Monneret G.. Early kinetics of the transcriptional response of human leukocytes to staphylococcal superantigenic enterotoxins A and GMicrob. Pathog.Year: 20094717117619591915
152.. Mempel M.,Lina G.,Hojka M.,Schnopp C.,Seidl H.P.,Schäfer T.,Ring J.,Vandenesch F.,Abeck D.. High prevalence of superantigens associated with the egc locus in Staphylococcus aureus isolates from patients with atopic eczemaEur. J. Clin. Microbiol. Infect. Dis.Year: 20032230630912743832


[Figure ID: toxins-02-01751-f001]
Figure 1 

Enterotoxin and enterotoxin-like genes in plasmids pIB485 and pF5 based on sequencing data deposited under the accession numbers indicated to the right of the figure. Note thatpIB485 also contains blaZ and cad resistance genes [94] and probably ser [40,95].

[Figure ID: toxins-02-01751-f002]
Figure 2 

Enterotoxin genes carried by prophages based on sequencing data deposited under the accession numbers indicated to the right of the figure.

[Figure ID: toxins-02-01751-f003]
Figure 3 

Staphylococcus aureus pathogenicity islands (SaPIs) carrying enterotoxin or enterotoxin-like genes. Modified from Novick and Subedi [105] and based on the accession numbers indicated to the right of the figure.

[Figure ID: toxins-02-01751-f004]
Figure 4 

Structure of two types of the vSaβ genomic island containing the enterotoxin gene cluster. Adapted from Baba et al. [108] and based on accession numbers indicated to the right of the figure.

[Figure ID: toxins-02-01751-f005]
Figure 5 

Structure of egc clusters. Modified from Thomas et al [28] and Collery et al. [114], and based on the accession numbers indicated to the right of the figure.

[Figure ID: toxins-02-01751-f006]
Figure 6 

Comparison of two allelic forms of SCC elements associated with seh. Modified from Noto and Archer [118] and based on the accession numbers indicated to the right of the figure.

[TableWrap ID: toxins-02-01751-t001] pii: toxins-02-01751-t001_Table 1.
Table 1 

General properties of SEs and SEls and genomic location of the encoding genes. See text for references. nd, not determined; a Emetic activity demonstrated in rabbits (SElL; [43]) or in the small insectivore Suncus murinus (SElP; [39]) but not in a primate model; b Hypothetical location in a prophage [48].

Toxin Molecular Mass (kDa) Emetic Activity Crystal Structure Solved Gene Accessory genetic element
SEA 27.1 yes yes sea ΦSa3ms, ΦSa3mw, Φ252B, ΦNM3, ΦMu50a
SEB 28.4 yes yes seb pZA10, SaPI3
SEC 27.5–27.6 yes yes sec SaPIn1, SaPIm1, SaPImw2, SaPIbov1
SED 26.9 yes yes sed pIB485-like
SEE 26.4 yes no see ΦSa b
SEG 27.0 yes yes seg egc1 (vSaβ I); egc2 (vSaβ III); egc3; egc4
SEH 25.1 yes yes seh MGEmw2/mssa476 seh/∆seo
SEI 24.9 weak yes sei egc1 (vSaβ I); egc2 (vSaβ III) ); egc3
SElJ 28.5 nd no selj pIB485-like; pF5
SElK 26.0 nd yes selk ΦSa3ms, ΦSa3mw, SaPI1, SaPI3, SaPIbov1, SaPI5
SElL 26.0 no a no sell SaPIn1, SaPIm1, SaPImw2, SaPIbov1
SElM 24.8 nd no selm egc1 (vSaβ I); egc2 (vSaβ III)
SElN 26.1 nd no seln egc1 (vSaβ I); egc2 (vSaβ III); egc3; egc4
SElO 26.7 nd no selo egc1 (vSaβ I); egc2 (vSaβ III); egc3; egc4; MGEmw2/mssa476 seh/∆seo
SElP 27.0 nd a no selp ΦN315, ΦMu3A
SElQ 25.0 no no selq ΦSa3ms, ΦSa3mw, SaPI1, SaPI3, SaPI5
SER 27.0 yes no ser pIB485-like; pF5
SES 26.2 yes no ses pF5
SET 22.6 weak no set pF5
SElU 27.1 nd no selu egc2 (vSaβ III); egc3
SElU2 (SEW) nd nd no selu2 egc4
SElV nd nd no selv egc4

[TableWrap ID: toxins-02-01751-t002] pii: toxins-02-01751-t002_Table 2.
Table 2 

Grouping of SEs and SEls based on amino acid sequence comparisons. Modified from Larkin et al. [21]. Enterotoxins encoded by the egc cluster are shown in bold. SEH (in parenthesis) has been placed within Group 1 or Group 5, depending on the author [29,49].

Group SEs and SEls
Group 1 SEA, SED, SEE, (SEH), SElJ, SElN, SElO, SElP, SES
Group 2 SEB, SEC, SEG, SER, SElU, SElU2
Group 3 SEI, SElK, SElL, SElM, SElQ, SElV
Group 4 SET
(Group 5) (SEH)

Article Categories:
  • Review

Keywords: Staphylococcus aureus, food poisoning, staphylococcal enterotoxins, emetic activity, superantigens, gene location.

Previous Document:  Chemical, physical and biological approaches to prevent ochratoxin induced toxicoses in humans and a...
Next Document:  Cholera-like enterotoxins and Regulatory T cells.