Staphylococcus aureus: The Toxic Presence of a Pathogen ...

Staphylococcus aureus: The Toxic Presence of a Pathogen ...

Current Medicinal Chemistry, 2009, 16, 4003-4019 4003Staphylococcus aureus: The Toxic Presence of a Pathogen ExtraordinaireE.A. Larkin 1,2 , R.J. Carman 3 , T. Krakauer 1 and B.G. Stiles* ,1,41 Department of Immunology, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick,Maryland, USA; 2 Hood College, Frederick, Maryland, USA; 3 TechLab, Inc., Blacksburg, Virginia, USA; 4 WilsonCollege, Chambersburg, Pennsylvania, USAAbstract: Staphylococcus aureus is a facultative, Gram-positive coccus well known for its disease-causing capabilities. Inparticular, methicillin and vancomycin resistant strains of S. aureus (MRSA and VRSA, respectively) isolated globallyrepresent daunting medical challenges for the 21 st Century. This bacterium causes numerous illnesses in humans such asfood poisoning, skin infections, osteomyelitis, endocarditis, pneumonia, enterocolitis, toxic shock, and autoimmune disorders.A few of the many virulence factors attributed to S. aureus include antibiotic resistance, capsule, coagulase, lipase,hyaluronidase, protein A, fibronectin-binding protein, and multiple toxins with diverse activities. One family of proteintoxins is the staphylococcal enterotoxins (SEs) and related toxic shock syndrome toxin-1 (TSST-1) that act as superantigens.There are more than twenty different SEs described to date with varying amino acid sequences, common conformations,and similar biological effects. By definition, very low (picomolar) concentrations of these superantigenic toxins activatespecific T-cell subsets after binding to major histocompatibility complex class II. Activated T-cells vigorously proliferateand release proinflammatory cytokines plus chemokines that can elicit fever, hypotension, and other ailmentswhich include a potentially lethal shock. In vitro and in vivo models are available for studying the SEs and TSST-1, thusproviding important tools for understanding modes of action and subsequently countering these toxins via experimentalvaccines or therapeutics. This review succinctly presents the pathogenic ways of S. aureus, with a toxic twist. There willbe a particular focus upon the biological and biochemical properties of, plus current neutralization strategies targeting,staphylcoccocal superantigens like the SEs and TSST-1.Keywords: Animal model, cytokine, immunotherapeutic, receptor, Stapylococcus aureus, superantigen, toxic shock, vaccine.1. INTRODUCTION TO A MICROBIAL TOXINFACTORYStaphylococcus aureus is one of the more formidable,disease-causing bacteria affecting humans and livestock [1-3]. The latin-derived genus species name means “goldencluster seed” for this facultative anaerobe that grows ingrape-like bunches yielding yellow colonies on agar. S.aureus was first discovered by Alexander Ogston in 1880following microscopy of a patient’s pus-filled abscess. Thebacterium readily colonizes skin as well as various mucosalsurfaces, and in most cases S. aureus provokes few problemswith its host. However, S. aureus is an opportunistic “bacterialstalker” that lingers within mammalian populations. Dependingupon the strain plus surrounding circumstances, thispathogen exploits an afforded opportunity (i.e. skin break,immunosuppressive state, pre-existing infection, penetrativewound, etc.) via numerous virulence factors that promotesurvival during the disease process, and then subsequentdissemination to a new host [4]. The focus of this review isupon one group of S. aureus virulence factors, the staphylococcalenterotoxins (SEs) and toxic shock syndrome toxin-1(TSST-1). These protein toxins abnormally stimulate, andthen critically cripple, an immune response of a colonizedhost by functionally knocking out specific T-cell subsets[5,6]. Unlike many bacterial toxins that directly harm hostcells (i.e. puncture membranes, shut down protein synthesis,destroy actin-based cytoskeleton, etc.), the SEs and TSST-1indirectly affect a host by triggering abnormal immune responses.*Address correspondence to this author at the Integrated ToxicologyDivision, Department of Immunology, Building 1425, Fort Detrick, Maryland21702-5011, USA; Tel: 301-619-4809; Fax: 301-619-2348;E-mail: bstiles@wilson.eduWhy be concerned with S. aureus and produced superantigenslike the SEs and TSST-1? As is alarmingly evidentthroughout the microbial world, there is also increasing resistanceof pathogenic S. aureus to antibiotics like methicillin(a beta-lactam that prevents cross-linking of cell-wall basedpeptidoglycan) and vancomycin (a glycopeptide that inhibitspeptidoglycan synthesis) [7]. The bacterium is linked to diversediseases, of which many can become life threateningfor anyone regardless of age and health status. Patients colonizedby antibiotic-resistant S. aureus (community or hospitalacquired) stay in the hospital longer and experiencehigher morbidity / mortality rates versus those infected withantibiotic-susceptible strains [8]. This sobering fact, linked tomedical economics, is further reinforced by data from variouscountries. An estimated 100 million dollars are spenteach year for managing antibiotic-resistant S. aureus in Canadianhospitals [9], in which there was a ten-fold increase incases from 1995 to 2004. Medical costs are even greater inother countries including the United States, where an estimated14 billion dollars were spent in 2003 to counter S.aureus infections [10]. There is no evidence suggesting thatthese numbers will decrease in the near, or distant, future andwe simply have few additional tools for effectively fightingS. aureus at this time. S. aureus represents a real health andeconomic concern throughout our society, today and tomorrow[11-13]. It is an understatement to say that we also needto alter our medical mindset to keep better pace with S.aureus. So, how do we deal more effectively with pathogenicS. aureus now? Perhaps this can be accomplished by employingnovel countermeasures (i.e. efficacious vaccines andimmunotherapeutics) in conjunction with modern infectioncontrol plans regularly practiced in medical facilities.A basic understanding of how a pathogen survives, flourishes,and evolves can logically lead to alternative means ofcontrol. As with many bacterial pathogens, protein toxins0929-8673/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

4004 Current Medicinal Chemistry, 2009 Vol. 16, No. 30 Larkin et a major role in various diseases of plants, animals, andhumans. At the molecular level, and among diverse bacterialgenera, evolution has led to a vast array of biologically similar(and also rather distinct) proteins commonly called toxins[14]. Targeting of these virulence factors for diagnosis, therapy,and vaccines makes good sense into the foreseeablefuture. S. aureus is rather industrious and a single strain canproduce multiple SEs (types A-U) that cause one of the mostprevalent forms of food poisoning throughout the world [15-17]. Typically, SE intoxication occurs after ingestion ofprocessed meats or dairy products contaminated with S.aureus by improper handling and subsequent storage at elevatedtemperatures. Once carelessly seeded into an accommodatingmedium, S. aureus grows and produces one ormore SEs that in low microgram / high nanogram quantitiescan elicit emesis and diarrhea approximately four hours afterconsumption [15,16,18]. Food poisoning due to SE is rarelyfatal and among the different serotypes, SEA is most commonlyassociated with illness because of an extraordinaryresistance towards proteolysis in the digestive tract[16,19,20]. Additionally, a role for SEs in antibioticassociateddiarrhea is quite plausible as antibiotic-resistant S.aureus could more readily colonize intestinal epitheliumdepleted of normal flora [21]. It is evident that various populationsthroughout the world are naturally exposed to S.aureus and these toxins, as demonstrated by SEA, SEB, andSEC seroconversion [22]. However, it is uncertain if humansnormally seroconvert via toxins ingested in contaminatedfood and/or colonization by a toxin-producing strain of S.aureus. In any event, S. aureus is omnipresent and humanpopulations throughout the world are continually exposed tothis bacterium and its toxins. Approximately thirty percent ofthe human population becomes normally colonized in thenares by S. aureus [23], and such a reservoir leads to an increasedrisk of staphylococcal infections.Toxic shock syndrome caused by TSST-1 of S. aureuswas first described in 1978 by Todd et al. [24], and laterlinked to menstruation plus use of highly-absorbent tampons[25-27]. Although TSST-1 was erroneously reported as anenterotoxin (SEF) [28], homogeneous TSST-1 lacks enterotoxicity[29]. TSST-1 intoxication, referred to as toxic shocksyndrome (TSS), consists of elevated serum levels of proinflammatorycytokines, rash, hypotension, fever, and multiorgandysfunction [30]. Nonmenstrual forms of TSS in men,women, and children are also attributed to other SEs followingS. aureus growth upon other body sites and in the bloodstream [31-33]. Recurring bouts of TSS can be common unlessthe offending strain of S. aureus is eliminated or kept atminimal growth. Toxin-specific antibodies play an importantrole in susceptibility to TSST-1-induced TSS [34], thus alack of specific immunoglobulins can portend susceptibilityto recurring bouts [35,36]. In addition to toxin-specific antibodies,individuals with antibodies against other S. aureusantigens are not as readily infected by S. aureus versus thosewith less robust immunity [37]. It is our opinion that experimentalvaccines targeting SEs or TSST-1 may break thehost’s immunological tolerance towards not only S. aureus,but perhaps other coinfecting pathogens too. Generally, tounderstand a biological event scientists often simplify aproblem to “one cause (microbe) = one effect (disease)”;however, with a pathogen like S. aureus producing superantigenictoxins that have adverse effects upon the immunesystem (described in detail below), superinfections due toother microbes are quite plausible. Vaccines against SEs orTSST-1 could be especially useful among high-risk populationsthat suffer recurring bouts of S. aureus–induced disease.The term "superantigen" was first proposed by Marrackand Kappler [38] to describe microbial proteins that activatea large population of specific T-cells, in contrast to activationby conventional antigens. Superantigens are ratherprevalent throughout Nature and produced by various bacterial,viral, and fungal pathogens that cause very diverse diseases[39-53] (Table 1). Such proteins are apparently “successful”virulence factors worthy of perpetuation, at leastfrom a pathogen’s perspective and evolution. Superantigensalso differ from conventional antigens in that they bind outsidethe peptide-binding groove of major histocompatibilitycomplex (MHC) class II, and exert biological effects withoutinternalization or proteolytic processing by antigenprocessingcells [38]. Evidently very few MHC class IImolecules must be occupied for initiating a superantigeninducedcascade involving T-cell stimulation, proinflammatorycytokine release, etc. [54]. Recognition of a superantigenby T-cell receptor (TCR) typically depends upon thevariable region of a chain (V), and not V and V combinationsof TCR used by conventional antigens. Superantigen-inducedactivation of the host’s immune system elicitsabnormally high levels of cytokines and chemokines, enhancesexpression / activation of cell-adhesion molecules,increases T-cell proliferation, and leads to T-cell apoptosis /anergy (Fig. 1). Sometimes though, reported superantigensprove not to be so as evidenced by Clostridium perfringensenterotoxin [55-57].Table 1. Microorganisms That Reportedly ProduceSuperantigensBacteria (superantigen)Mycobacterium tuberculosis (MTS)Mycoplasma arthritidis (MAM)Staphylococcus aureus (SEA-SEU, TSST-1)Streptococcus dysgalactiae (SPEGG)Streptococcus pyogenes (SPEA, C, G, H, I, J)Yersinia enterocolitica (YES)Yersinia pseudotuberculosis (YPMa, YPMb, YPMc)VirusesCytomegalovirus (?)Herpes Virus (M1)Mouse Mammary Tumor Virus (?)Rabies Virus (Nucleocapsid)FungiCandida albicans (Int1).

Staphylococcus aureus Superantigens Current Medicinal Chemistry, 2009 Vol. 16, No. 30 4007site on SEA is of lower affinity and located within the N-terminus (Phe47), which in turn interacts with Gln18 foundon the chain of HLA-DR. SEA cooperatively binds as adimer to HLA-DR, thus cross-linking two MHC class IImolecules necessary for cytokine expression [87]. Dimerizationof other staphylococcal superantigens, like SEB orSECs, as well as that for MHC class II molecules can play animportant role in biological activity in vivo [88,89]. Evidentlythere are few conformational changes that occurwithin SEB, or the class II molecule, after forming a heteromericcomplex [88].The N-termini of SEB and TSST-1 have also been identifiedas MHC class II binding sites via studies with toxin mutantsand monoclonal antibodies [71,72,90]. Crystal structuresof SEB or TSST-1 complexed with HLA-DR1 definitivelyreveal different binding mechanisms, although thesetoxins share the same contact residues on the chain ofMHC class II [88,91]. SEB binds exclusively to the chainof HLA-DR1 and is not affected by associated peptide, unlikeTSST-1 which interacts with the and chains ofHLA-DR1 or murine IA, as well as the C-terminus of certainbound peptides.Further examination of SEB - HLA-DR1 co-crystals revealsthat nineteen SEB residues and twenty-one residues ofHLA-DR1 are intimately involved in complex formation[88] (Fig. 3). Some of these interactions are hydrophobic andoccur via Phe44, Leu45, and Phe47 of SEB with HLA-DR1residues Tyr13, Met36, Ala37, Leu60, Iso63, and Ala64.Fig. (3). Crystal structure of SEB complexed with HLA-DR1 (2.7 Å resolution) [88]. Data derived from the Protein Data Bank of theResearch Collaboratory for Structural Bioinformatics using PyMOL (DeLano Scientific LLC) for molecular modeling. Panels A and B representdifferent orientations of the SEB - HLA-DR1 complex to better expose residues involved in binding. White-numbered residues arefrom SEB and black-numbered residues are from HLA-DR1.

4008 Current Medicinal Chemistry, 2009 Vol. 16, No. 30 Larkin et al.Such hydrophobic-based bonds are lost with TSST-1, whichcontains a Ser instead of the Phe44 in SEB. SEB (Glu67)forms a salt bridge with HLA-DR1 chain (Lys39), whileSEB Tyr89 and Tyr115 provide critical hydrogen bonding toreceptor. This interaction is also absent for TSST-1 withHLA-DR1, as the toxin has residue substitutions preventingeffective interactions with Lys39 of the chain. HLA-DR1residues Tyr13, Gln18, and Lys67 may also bind to Gln43,Phe44, Leu45, and Tyr46 of SEB. Within the SEB disulfideloop (in particular residues Gln92, Tyr94, Phe95, Ser96)there is contact with HLA-DR1 residues 60-68. When complexed,the interface formed between class II and SEB respectivelyencompasses 780 Å 2 and 760 Å 2 which are verysimilar to typical antigen-antibody (epitope-paratope) combiningsites [88].In addition to MHC class II binding, and like other microbialsuperantigens, the SEs as well as TSST-1 also interactwith the TCR V chain via a groove formed between thetwo toxin domains [92-95]. Binding of this superantigenclassII complex leads to TCR clustering, subsequent signaling,and potentially detrimental release of proinflammatorycytokines / chemokines from antigen presenting cells (i.e.macrophages plus monocytes) and T cells [96,97]. Thesetoxins each bind a distinct repertoire of V-bearing T-cells,thus revealing a unique biological “fingerprint” useful forconfirming a diagnosis of TSS [98,99]. One very unusualexception has been noted, as SEH evidently stimulates Tcells in a V-specific mode [100]. It is uncertain why SEH isunique from all other SEs tested to date, but this is likelylinked to T-cell presentation after the toxin complexes withMHC class II. Additionally, binding of SEH to MHC classII-bearing cells occurs with remarkably high affinity (subnanomolar)versus other staphylococcal superantigens [101].As per different V specificities of the SEs and TSST-1(Table 3), it is logical that MHC class II / TCR contacts differfor each toxin. As an example of this diversity, mutagenesisof the SECs reveals that a Tyr or Val (residue 26) differentiallyaffects V3 and 13.1 interactions [102]. Val91ofSEC2 also impacts binding to TCR, but an equivalent aminoacid is not found in either SEA (Tyr94) or SEB (Tyr91). Molecularmutagenesis of SEA into SEE, or SEE into SEA, isinteresting from a T-cell stimulation perspective. A comprehensivestudy with these toxins reveals that only two residues(Ser206 and Asn207) of SEA, when switched to thosefound in SEE (Pro206 and Asp207) or vice versa, generates atoxin with the V stimulatory profile like the other [103].Additionally, orientation and binding affinity of superantigenwith the -chain of MHC class II affect TCR V interactions.The binding affinity between TCR and a SE is relativelyweak (K d ~10 -6 ), but this interaction is strengthened byprior binding of toxin to MHC class II [94]. SEB residuesthat interface with TCR include solvent-exposed Asn23, Asn60, Tyr61, and regions of the disulfide loop (Cys93-Cys113)(Fig. 4). A cooperative effect is also observed for SEA withhost TCR and MHC class II, ultimately enhancing tricomplexstability that stimulates macrophages, monocytes, and Tcells [95]. In the case of TSST-1, T-cell activation may beinfluenced by contact between the C-terminus of TSST-1with peptide lying in the antigen-binding groove of HLA-DR[91]. Specifically, histidines 132, 135, and 140 of TSST-1are important for TCR interactions and subsequent release ofproinflammatory cytokines from T cells [104-106].It is clear that the superantigenic potential of these S.aureus toxins results from a cooperative process betweenmicrobial toxin and cell-surface receptors, which ultimatelytriggers a detrimental response within the host. From a microbiologist’sor biochemist’s perspective, the SEs andTSST-1 are rather complicated protein toxins via their intricateinteractions with multiple cell types and different receptorsthat negatively impact the immune system. The biologicaleffects of SEs and TSST-1 are intimately linked to a myriadof host-derived effectors (i.e. proinflammatory cytokinesand chemokines) that, in large enough concentrations, cancause great harm to a host. Normally, such effector moleculesare meant to afford host protection towards a plethoraof pathogenic invaders encountered on a daily basis. In manyways, a vigilant immune system that defends against life’slittle challenges can ironically become one’s demise fromwithin.4. IN VIVO EFFECTS OF SES AND TSST-1: AMULTIFACTORIAL EVENTIn humans and nonhuman primates, SEs can elicit anemetic response and in rare cases toxic shock following ingestionof very low microgram quantities [15,16]. In contrast,TSST-1 does not cause emesis after ingestion but canTable 3.Human V Specificity of Select SEs and TSST-1SEA (V 1.1, 5.1, 5.2, 5.3, 6.3, 6.4, 6.9, 7.2, 7.3, 7.4, 7.9, 8, 9.1, 16, 18, 21.3, 22, 23)SEB (V 3, 6.4, 12, 13.2, 14, 15, 17, 20)SEC1 (V 3. 6.4, 6.9, 12, 13.2, 14, 15, 17, 20)SEC2 (V 12, 13.1, 13.2, 14, 15, 17, 20)SED (V 1, 5, 6.9, 7.4, 8, 12)SEE (V 5.1, 6.1-6.4, 6.7, 6.9, 8.1, 16, 18, 21.3)SEG (V 3, 12, 13.1, 13.2, 13.6, 14, 15)SEI (V 1, 5.1, 5.2, 5.3, 6, 23)SELL (V 5.1, 5.2, 6.7, 7, 9, 16, 22)SELM (V 5.1, 5.2, 5.3, 6, 18, 21.3, 23)TSST-1 (V 2, 4)Data derived from multiple references [1,40,99,215].

Staphylococcus aureus Superantigens Current Medicinal Chemistry, 2009 Vol. 16, No. 30 4009Fig. (4). Crystal structure of SEB complexed with V 8.2 of mouse TCR (2.4 Å resolution) [93]. Data derived from the Protein DataBank of the Research Collaboratory for Structural Bioinformatics using PyMOL (DeLano Scientific LLC) for molecular modeling. The numberedresidues in the green region are from SEB.evoke systemic shock via growth of toxigenic S. aureus onmucosal surfaces [29,107]. Unlike a number of other enterotoxins,specific cells and receptors in the intestinal tract havenot been unequivocally linked to oral intoxication by a SE.After many decades of research, it is disappointing that wedo not have a better understanding of toxin receptor(s), trafficking,and overall intoxication process leading to entericill-effects. Much effort indeed has been spent by many laboratoriesupon the superantigen aspects of these toxins andTSS, which may or may not play an important role in foodpoisoning.In regards to enteric effects of the SEs, when SEA orSEB are injected intraperitoneally there is distal induction ofFos (a transcription-linked cell activator) throughout thebrain via vagus nerve stimulation from the gut. Such datasuggest that the peripheral presence of a SE affects the centralnervous system [108,109]. Capsaicin, a small molecularweight (305 daltons) metabolite in hot chili peppers, depletespeptidergic sensory nerve fibers and diminishes SE effects inmammals [110,111]. Similar results (capsaicin-induced inhibitionof vagal nerve stimulation) are evident for other gutoriginating,protein toxins like E. coli heat stable enterotoxin[112] and Clostridium difficile toxin A [113]. SE communicationdirectly (or indirectly) with the vagus nerve via MHCclass II-bearing cells may be linked to fibrous vagus bundlesfound throughout the abdomen [114]. From a therapeuticperspective, experiments involving the central or peripheralnervous systems and SEs are clearly lacking in the literature.Various investigators have attempted to locate a specificemetic domain within the SEs, but findings have been limitedand equivocal. Single residue changes in SEA(Leu48Gly) and SEB (Phe44Ser) result in molecules that stillelicit emesis, yet do not bind MHC class II or cause T-cellstimulation [115]. The disulfide loop in various SEs, whichis absent in TSST-1, may be responsible for the emetic activityof SEs but that too remains controversial between differentlaboratories [116,117]. Carboxymethylation of histidineson SEA [118] or SEB [119] generates proteins devoid ofenterotoxicity, or skin reactivity [120,121], yet these modifiedtoxins still retain superantigenicity. The chemicallymodifiedSEB also inhibits, in a presumed competitive fashionfor receptor, the enteric effects of wild-type SEB whenconcomitantly given orally to nonhuman primates [121].Lack of enterotoxicity attributed to carboxymethylsubstitutedSEA is not due to enhanced degradation by gastricproteases [122], thus suggesting that this modified formof SEA retains a native conformation naturally resistant toproteolysis. Analysis of each histidine and effects upon SEAinducedemesis plus superantigenicity reveals that His61 isimportant for emesis, but not T-cell proliferation [122];therefore, demonstrating that an emetic response and superantigenicityrepresent distinct properties of the toxin. Anothergroup used antibodies that prevent SEA-induced emesisby targeting SEA residues 121-180, a region lacking thedisulfide loop (Cys91-Cys105) and histidines [123].SE-induced stimulation of mast cells and subsequent releaseof cysteinyl leukotrienes (eicosanoid mediators of inflammation)cause emesis, as well as skin reactions, in primates[124,125]. Murine V8 + T-cells found within intestinalPeyer’s patches are adversely affected by orallyadministeredSEB, as determined by a subsequent lack of in

4010 Current Medicinal Chemistry, 2009 Vol. 16, No. 30 Larkin et al.vitro stimulation by the same toxin [126]. Within four hoursof ingestion, mRNA induction for IFN is increased ten-foldin mucosal (versus peripheral) V8 + T-cells. Elevated levelsof IFN can lead to dysfunction of the intestinal epithelium(i.e. barrier breakdown) that ultimately exacerbates illness.Superantigen presentation to T cells in the Peyer’s patcheslikely occurs via microfold (M) cells specialized in antigentransport from the intestinal lumen. Superantigen-inducedeffects, due to S. aureus or other microbes, also seem to playan important role in inflammatory bowel disease [127-129].A recent study with severe combined immunodeficient(SCID) mice suggests that regulatory T-cells critically participatein SEB-induced inflammation of the intestines [130].Effects of the SEs upon mucosally-located T cells mayalso explain earlier results showing that SE ingestion bynonhuman primates yields transient resistance to an evenhigher dose of the same toxin [131]. However, this effect isnot evident when these animals are given another SE serotypeorally and perhaps such findings are due to toxinspecificstimulation of unique V-bearing T-cells. In additionto toxin-specific resistance elicited by one oral dose of aSE, chronic intravenous exposure to SEA can functionallydelete all V-reactive T-cells in mice [132]. Such strikingalterations of the immune system could perhaps induce animmunocompromised state and transiently increase susceptibilityto additional infections. Footpad injections of SEB inmice also cause a dose-related, immunological toleranceamong V8 + T-cells [133]. Another study in mice givenwild-type SEA intranasally reveals resistance to a subsequentlethal challenge (intraperitoneal) with SEA, but not a heterologoussuperantigen like TSST-1 [134]. A recombinantform of SEA devoid of superantigenicity, when given intranasally,does not afford the same protection towards wildtypeSEA. This effect is not due to toxin-specific antibody ordepletion of SEA-reactive T-cells, but there is a significantincrease in serum levels of IL-10. Previous studies show thatIL-10 affords protection against SE-induced effects [135];however, a recent study of neonatal TSS triggered by TSST-1 shows that neonates with this disease have elevated levelsof IL-10 versus individuals without TSS [136]. Overall, existingliterature suggests that high circulating levels of IL-10lead to reduced severity of superantigen-based disease.Circulation of SEs or TSST-1 from a S. aureus infectionsite (i.e. intestines, mucosa, skin), or following ingestion oftoxin in classic food poisoning, could have more profoundeffects upon the host versus if the toxin remains localized.Studies employing a human colon monolayer (Caco-2 cells)show transcytosis of SEA, SEB, and TSST-1, while in vivoresults (mice) reveal that SEB enters the bloodstream morereadily than SEA after ingestion [137]. A more recent studysuggests that a superantigen-conserved, dodecapeptide fromTSST-1 (Phe119-Asp130) plays a role in epithelium penetrationand toxicity in vivo [138]. Overall, such data suggestthat these toxins cross the gastric or vaginal mucosa and subsequentlycirculate throughout the body. In vitro, these toxinsare not cytotoxins that directly kill human intestinal cellslike Henle 407 [139]. However, incubation of a human colonicmonolayer (T84 cells) with SEB and peripheral bloodmononuclear cells (PBMC) increases ion flow across thecell-based barrier, thus suggesting indirect toxin effects upongut mucosa via the immune system and released proinflammatorycytokines [140]. A cytokine protective against variousbacterial superantigens in vivo, IL-10 (but not IL-4),dose-dependently inhibits permeability of T84 cell monolayersin vitro when added before or concomitantly with SEB[135,140-142].As previously discussed, superantigen interactions withMHC class II and selected TCR V enable the SEs andTSST-1 to perturb the immune system towards releasinghigh concentrations of proinflammatory cytokines. Anotherresult of such perturbations is that the SEs and TSST-1 arepyrogenic in humans, nonhuman primates, ferrets, and rabbits[143-145]. This is largely attributed to elevated levels ofproinflammatory cytokines that include synergistic actions ofIL-1 and tumor necrosis factor alpha (TNF), which ultimatelyinduce fever via the hypothalamus [146]. Serum levelsof IFN, IL-2, and IL-6 also increase after toxin exposure.IFN augments immunological responses by increasingthe MHC class II levels on antigen presenting, epithelial, andendothelial cells. IFN also upregulates expression of TNFand IL-1 receptors, that when bound by ligand, increasesadhesion molecules on endothelial cells as well as promotesleukocyte binding plus recruitment. Shock induced by superantigensultimately results from cumulative ill-effects ofproinflammatory cytokines adversely affecting various organsthroughout the host [147].Animal Models for SEs and TSST-1: Necessary StepsToward a Better UnderstandingMice are often used for obtaining a basic understandingof how toxins (and other biologically-active substances) interactin vivo, which includes the immunological mechanismsthat promote superantigen-mediated shock [148-156].Although these animals curiously lack an emetic response,they are cost-effectively ideal for in vivo screening of potentialvaccines and therapeutics. Mice are naturally less susceptibleto SEs and TSST-1, versus humans, because of loweraffinity for murine MHC class II. Potentiating agents like D-galactosamine, actinomycin D, lipopolysaccharide (LPS,also known as endotoxin), and even viruses (i.e. influenza orlymphocytic choriomeningitis) amplify the toxic effects ofsuperantigens in mice. Many of our studies involve an LPSpotentiatedmouse model [104,141,150], as various in vitroand in vivo assays reveal a natural synergy (many log-fold)between SEs / TSST-1 and LPS [157-162]. As little as twomicrograms of LPS alone in humans can cause endotoxicshock [163], thus only picogram quantities of endotoxin inconjunction with a superantigen can cause quite severe, lifethreateningeffects [164]. Upon considering the many Gramnegativebacteria that compose the intestinal flora, and increasednumbers found in the vaginal flora of TSS patients,odds of this synergy naturally occurring are really quite high[164,165]. In concordance with human data, there is a goodcorrelation between increased serum levels of IL-1, IL-2,TNF, and/or IFN with SEA-, SEB-, or TSST-1-inducedshock in mice [148-160]. These efforts coincide with othersinvolving SEA and genetic knockout mice deficient in IFNor the p55 receptor for TNF [141]. In addition to potentiationof SE effects in mice by other compounds, it has beenrecently reported that C3H/HeJ mice (non-LPS responders)lethally respond to one or two timed doses of SEB (seven

Staphylococcus aureus Superantigens Current Medicinal Chemistry, 2009 Vol. 16, No. 30 4011micrograms total) given intranasally [166]. IL-2 and monocytechemoattractant protein-1 (MCP-1) play a critical rolein this particular model.Transgenic mice expressing human HLA-DQ6 and CD4succumb to normally sublethal amounts of SEB (i.e. D-galactosamine potentiation in wild-type animals), with serumlevels of TNF correlating with lethal shock [154]. Transgenicmice expressing human HLA-DR3 and CD4 lethallyrespond to SEs without a potentiating agent, perhaps affordingyet another model for future in vivo studies [155]. Fewerparameters (i.e. potentiating components) used in a modelenable easier interpretation of results, especially for therapeutic-basedstudies in vivo. When SEB is incubated withPBMC from HLA-DR3/CD4 mice, more IL-6 and IFN arereleased relative to similarly-treated PBMC from nontransgeniccontrols. These data suggest that proinflammatorycytokines, like those elevated in other animals or humans,also play an important role during SE-induced shock intransgenic mouse models.In addition to lethality as an endpoint for SE or TSST-1intoxication, temperature is a readily measured parameter ofshock-induced illness. Historically, rabbits afford an attractivemodel for SE- and TSST-1-induced shock with eithertemperature or lethal endpoints [162,167,168]. Similar tohumans with TSS [157], rabbits exposed to TSST-1 or SEBhave subsequently heightened levels of LPS in the bloodstream[169,170]. Increased levels of circulating LPS may bedue to toxin-elicited impairment of liver function [162,171].Goats have also been used for studying the in vivo effects ofTSST-1 and SEB, involving temperature fluctuations followingintravenous administration [172]. Temperature is alsoreadily measured with LPS-potentiated SE and TSST-1 inmice (BALB/c or C57BL/6) implanted with a subcutaneoustransponder [141] or telemetry device [173]. In such nonlethalmodels, mice experience a significant decrease in temperature(there was never any detectable increase) within tenhours of intoxication. Additionally, C3H/HeJ mice that aredual-dosed intranasally with SEB also experience measurabletemperature fluctuations [166].Finally, an unusual animal model involves ferrets givenSEB orally, with end results being emesis and rapid fever[145]. Milligram quantities of toxin are however necessaryfor an effect versus microgram amounts commonly used inmice, rabbits, or nonhuman primates. In addition to potentialavailability issues of these unique laboratory animals, theferret model seems less feasible than others for vaccine ortherapeutic discovery based upon toxin amounts needed for abiological effect.5. SUPERANTIGEN TRICKERY: A SUBVERSIVEPUSH TOWARDS AUTOIMMUNITYAs superantigens specifically activate V-bearing T cells,some that are normally quiescent and autoreactive, the dangerof host autoimmunity is real. Arthritis, psoriasis, atopicdermatitis, collagen vascular disease, as well as inflammatorybowel disease have all been linked (to varying degrees)with microbial superantigens like the SEs and TSST-1 [127-129,174-179]. Although many proinflammatory cytokines inhigh concentrations can be deleterious for the host, IL-10actually plays a protective role by preserving a self-tolerantstate within the host via downregulating macrophage andmonocyte functions [180].When S. aureus colonizes skin, a toxic byproduct ofgrowth (i.e. SEB) can readily inflame the human epidermisperhaps by degranulation of cutaneous mast cells [120,181].Severe atopic dermatitis induces apoptotic T-cells, which canhave dire consequences for the host as evidenced by chronicinfections and disease severity [182]. However, versus normalcontrols, a mild case of dermatitis induces hyperreactiveT-cells towards SEB which is concomitantly associated withelevated levels of proinflammatory cytokines. Specific IgEagainst SEs and TSST-1 is also evident in atopic dermatitispatients, but not so in others even when colonized by S.aureus, thus suggesting additional linkage of these toxins tothis disease [183]. Evidently the density of S. aureus on skincorrelates with development of atopic dermatitis [184];therefore, multiple factors such as environment, hygiene,resident flora, and antibiotic usage all play important roles indevelopment of this disease. Among cancer patients, radiationtherapy may also induce a very severe dermatitis linkedto prior colonization by S. aureus [185].6. ANTIBODY-MEDIATED PROTECTION AGAINSTSES AND TSST-1: VACCINES PLUS ANTIBODY-BASED THERAPEUTICSTo date, there is remarkably no Food and Drug Administration(FDA)-approved therapeutic (in addition to commonly-usedantibiotics) or vaccine to counter S. aureus. Thisis a particularly pressing issue as per increased isolation oftoxin-producing, antibiotic-resistant strains of S. aureusamong select (and very susceptible!) populations, that include:1) dialysis, trauma, intensive care, as well as immunocompromisedpatients; 2) patients with surgical implants andparticularly ventriculoperitoneal shunts; 3) nursing homeresidents; 4) diabetics; 5) healthcare providers; 6) militarypersonnel; and 7) premature babies [186,187]. Veterinaryvaccines for S. aureus have been developed that afford reasonableprotection against mastitis in cattle, but the use ofeither whole bacteria (formalin killed and chemicallymutagenized)or crude cell lysates as inoculum for humans israther remote [188-190].Regarding vaccines for humans against S. aureus, an experimentalproduct called StaphVAX ® targets capsular polysaccharideserotypes 5 and 8 (found on many human plusveterinary clinical isolates) and has been thoroughly testedthrough phase III clinical trials [191]; however, this vaccineultimately proved less than efficacious [190]. StaphVAX ® iscomposed of S. aureus polysaccharides conjugated to Pseudomonasaeruginosa exotoxin A (recombinantly detoxifiedform). Evidently further studies are planned to include otherantigens with this product, such as the cell-surface polysaccharide336, alpha toxin, and Panton-Valentine leukocidin. Itis possible that surface-targeting antibodies are not efficaciousbecause the bacterium may survive in phagocytes evenafter binding of opsonizing antibodies [190]. Additionally,capsular antigens (serotypes 5 and 8) are present during stationary,but not growth, phases of S. aureus in vitro. It isuncertain if this is also the case during an infection, but if so,

4012 Current Medicinal Chemistry, 2009 Vol. 16, No. 30 Larkin et al.perhaps it would be better from a vaccine perspective to targetantigens expressed during the early growth phase of S.aureus. For reasons not totally understood, the capsularpolysaccharide-based vaccine for S. aureus falls short ofsimilar-based vaccines used successfully against other bacterialpathogens like Haemophilus influenzae and Streptococcuspneumoniae.To neutralize other S. aureus virulence factors like theSEs and TSST-1, there are at least three important targets:(1) TCR - toxin - MHC class II interactions; (2) accessory,co-stimulatory, or adhesion molecules involved in activationand effector functions of T-cells; and (3) cytokine release byactivated T-cells as well as macrophages. Inhibition of all, orjust one, of these three targets has been reported both in vitroand in vivo, thus representing viable strategies towards curbingthe biological effects of these bacterial toxins.Various groups have developed experimental vaccinesfor the SEs and TSST-1. This seems like a wise strategy, aspreexisting antibodies against SEs and TSST-1 play an importantrole in disease outcome [34-36] and the use of intravenousimmunoglobulins (IVIG) has proven efficacious inhumans after the onset of staphylococcal or streptococcaltoxic shock [192,193]. Given this wealth of information, it islogical that vaccination spurring a targeted humoral responsemight be useful for preventing TSS caused by SEs andTSST-1. Recombinantly-attenuated SEA, SEB, and TSST-1not binding to MHC class II and/or specific V-bearing TCRmolecules represent experimentally successful vaccines preventingtoxic shock in different animal models [194-198].These vaccines, when given either parenterally or mucosally,have proven efficacious against a toxin challenge or S.aureus infection in various animal models. Other murine andnonhuman primate studies with formalin-inactivated SEBreport protection towards a homologous toxin challenge followingparenterally-, or mucosally-, administered vaccine[199,200]. However, subsequent studies have demonstratedthat formaldehyde treatment of proteins adversely affectsprocessing and subsequent presentation to the immune system[201], especially if the modified protein represents amucosal immunogen [202].From a vaccine perspective, antigens other than the SEsand TSST-1 may be important for mitigating various diseasescaused by S. aureus. In the end, vaccines containing afew select virulence factors possessing diverse biologicalactivities will likely be most efficacious. There are multipleexamples of dissimilar S. aureus antigens efficacious againstthe bacterium in various animal models, when used as a soletarget antigen, such as: 1) iron surface determinant B whichis a conserved iron-sequestering protein on the cell surface[203]; 2) recombinantly-attenuated alpha toxin unable toform pores in cell membranes [204]; 3) glutathione S transferase- TSST-1 fusion using a TSST-1 molecule incapableof binding TCR [205]; 4) staphylococcal-conserved, glyceraldehyde-3-phosphatedehydrogenase homologs [206]; and5) a unique vaccine consisting of an adhesin protein fromCandida that structurally mimics a fibrinogen / fibrin bindingprotein (clumping factor A) of S. aureus [207]. Protectionafforded by the latter vaccine is more T-, versus B-, cellmediated while a humanized monoclonal antibody targetingS. aureus clumping factor A is readily tolerated by patientsand preliminary results show efficacy [208]. Even thoughthese various studies provide hope, there is still much morework to be done towards generating an efficacious, FDAapprovedvaccine against S. aureus. A reduction in nasalcarriers of S. aureus would logically diminish bacterialspread throughout a population, thus a vaccine that stimulatesmucosal immunity might be more beneficial versus thatpredominantly activating a systemic immune response.Besides active vaccination against S. aureus, the use ofimmunotherapeutics is particularly appealing for the medicalcommunity. To address these needs there have been to datethree human antibody products used in clinical trials; however,none has received FDA approval for various reasons[190]. These reagents vary in targeted antigens, and include:1) AltaStaph ® – human polyclonal antiserum (following vaccinationwith aforementioned StaphVAX ® ) against S. aureuscapsular polysaccharides 5 and 8; 2) Veronate ® (also knownas INH-A21) – enriched antibodies from human sera targetingstaphylococcal adhesins like clumping factor A; and 3)Pagibaximab ® – humanized mouse antibody (monoclonal)targeting lipoteichoic acid, a cell wall / membrane constituentof S. aureus. In a non-commercial venture, LeClaire etal. [209] described the protective effects of chicken immunoglobulinY generated against SEB in a nonhuman primatemodel. Passive transfer of this antitoxin up to four hoursafter SEB exposure proved quite effective. An advantage ofthis antibody type, versus those derived from other nonhumanspecies, is less reactogenicity in humans.In summary, there is a growing demand for efficaciousvaccine- and therapeutic-based antibodies targeting S.aureus. Increasing antibiotic resistance of S. aureus isolatedfrom around the world, and a decreasing ability to effectivelyfight these microbes in clinical settings, are major drivingforces for this emerging market. A successful product wouldlikely block attachment of S. aureus to host tissue, neutralizemultiple toxins, and/or enhance both cell-mediated plus humoralimmunity.7. CONCLUDING REMARKSS. aureus is a formidable pathogen producing variousprotein superantigens (i.e. SEs plus TSST-1) that interactwith MHC class II and TCR molecules on host cells. Suchbinding events subsequently cause the immune system toover react through hyperproduction of various immunomodulatorslike proinflammatory cytokines and chemokines.Amino acid homologies, as well as similar conformationsplus biological activities, among the SEs and TSST-1 suggestcommon evolutionary paths. Superantigens produced byother bacteria, viruses, and even fungi further imply thatthese proteins afford a survival advantage that perhaps includesdelayed clearance from a host [210,211]. To geneticallyconserve and then expend valuable energy for synthesizingsuperantigens from one generation to the next impliesa biological success within the microbial world. Perhapsthere are other activities attributed to these molecules thathave not yet been defined, as per the limits of existing assayscommonly used in research laboratories today?Hyperstimulation of T-cells, release of unhealthy levelsof cytokines plus chemokines, and subsequent immunosup-

Staphylococcus aureus Superantigens Current Medicinal Chemistry, 2009 Vol. 16, No. 30 4013pression are all induced by the SEs or TSST-1. Interferencewith any of these steps should prevent, or at least mitigate,toxic manifestations of these staphylococcal superantigensand thus decrease morbidity and mortality attributed to S.aureus infections. Antibody-based interventions targeting theSEs and TSST-1 could occur via various aforementionedvaccines and/or immunotherapeutics. To date, such medicalreagents are only experimental but some day will hopefullybecome clinically-viable options for physicians.To counter S. aureus, it is likely that targeted virulencefactors in addition to the SEs and TSST-1 will be useful.Clearly, as a society, we must take more aggressive actiontowards countering S. aureus as evidenced by the pathogen’sincreasing antibiotic resistance, role in multiple diseases, andestablished prevalence throughout the world. We believevaccine and immunotherapeutic attempts, although experimental,are positive steps in the proper direction. Variousclinical trials focused upon clearance of pathogenic S. aureusfrom humans, with less than stellar results, perhaps suggestwe need to expand our approaches to more than one or twovirulence factors. By medically attacking multiple S. aureustargets there will likely be better results with, or without, theuse of antibiotics whose efficacy is being eroded at an alarmingrate. Furthermore, S. aureus is just one of many pathogensthat we are slowly losing our ability to control withcurrent medicinal tools. It really is time to think, and then do,outside of the existing medical box we have now paintedourselves into as we rapidly end this first decade of the 21 stCentury.ACKNOWLEDGEMENTSFunding for this, and other related projects, has beengenerously provided by the Defense Threat ReductionAgency (DTRA) and Wilson College. This research wassupported in part by an appointment (EAL) to the PostgraduateResearch Participation Program at the U.S. Army MedicalResearch Institute of Infectious Diseases. Administrationwas provided by the Oak Ridge Institute for Science andEduation through an interagency agreement between the U.S.Department of Energy and the U.S. Army Medical Researchand Materiel Command.Expert help with software was kindly provided by Dr.Corinne Zeitler regarding the generation of protein structures.Critical reading of the manuscript by Sam Umbaughwas greatly appreciated.CONFLICTS OF INTERESTThe authors report no conflicts of interest, and all expressedopinions are those solely of the authors and do notreflect in any way the official views of the United Statesgovernment.ABBREVIATIONSIVIG = intravenous immunoglobulinIFN = interferon gammaIL= interleukinLPS = lipopolysaccharideMHC class II = major histocompatibility complex class IIPBMC = peripheral blood mononuclear cellsSE= staphylococcal enterotoxinTSST-1 = toxic shock syndrome toxin-1TCR = T-cell receptorTNF = tumor necrosis factorREFERENCES[1] Uchiyama, T.; Imanishi, K.; Miyoshi-Akiyama, T.; Kato, H. 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