Staphylococcus Aureus Exfoliative Toxins: How They Cause Disease

View metadata, citation and similar papers at core.ac.uk brought to you by CORE To cite this article: JID 122:1070–1077, 2004 provided by Elsevier - Publisher Connector Published by the ology Progress in Dermatology Editor: Alan N. Moshell, M.D. Staphylococcus aureus exfoliative toxins: How they cause disease. Lisa R.W. Plano, M.D., Ph.D. Departments of Pediatrics and Microbiology & Immunology University of Miami School of Medicine, Miami, Florida Abbreviations: cell surface molecules associated with adhesion and BI- bullous impetigo multiple antibiotic resistances including methicillin and ET- exfoliative toxins vancomycin resistance (Centers for Disease Control and EDIN- epidermal cell differentiation inhibitor Prevention, 1997; 2000a; 2000b), all contributing to the ETA- exfoliative toxin A (epidermolysisn A, exfoliatin A) pathogenicity of these organisms. A minimum of 34 ETB- exfoliative toxin B (epidermolysisn B, exfoliatin B) different extracellular proteins are produced by S. ETD- exfoliative toxin D (epidermolysisn D, exfoliatin D) aureus, and many of these have defined roles in the PF- pemphigus foliaceus pathogenesis of their associated diseases (Iandolo, SSSS- Staphylococcal scalded skin syndrome, (pemphi- 1989). Infectious conditions caused by these organisms gus neonatorum, dermatitis exfoliativa neonatorum, can be divided into three major categories; (i) superficial Ritter’s disease) skin infections, skin abcesses and wound infections TEN- toxic epidermal necrolysis including bullous impetigo (BI) and furuncles, (ii) systemic or infections of deep seeded tissues including osteomyelitis, endocarditis, pneumonia and sepsis, and Introduction (iii) conditions caused by intoxication with one of the General Microbiology: Staphylococci are hardy excreted toxins. Among the conditions caused by intoxi- Gram-positive cocci found as bacterial pathogens or cation with an exotoxin are toxic shock syndrome caused commensal organisms in both humans and animals. by toxic shock syndrome toxin (TSST-1) (Bloster-Hauta- These organisms are resistant to harsh conditions and maa et al, 1986), staphylococcal food poisoning caused can be recovered from non-physiologic environments up by the staphylococcal enterotoxins (SE) (Bergdoll, 1972; to months after inoculation. They grow easily under Bergdoll, 1983; Bergdoll et al, 1981) and staphylococcal numerous conditions and are classified based on coagu- scalded skin syndrome (SSSS) mediated by the exfolia- lase activity. Coagulase positive strains are classified as tive toxins (ETs), primarily ETA and ETB (Arbuthnott et Staphylococcus aureus. Approximately 35% of the al, 1972). This discussion will focus on the exfoliative general population are commensal nasal carriers and toxins of S. aureus and the mechanism by which they most newborns will be colonized within the first week of cause disease in humans. life (Dancer and Noble, 1991). Of the staphylococci, S. aureus is the most significant pathogen causing both General characteristics of the exfoliative toxins. human and animal diseases. S. aureus causes a wide There are two major biologically and serologically variety of infections acquired in both the community and distinct S. aureus ET isoforms that are primarily respon- hospital settings. It is the most common cause of sible for the skin manifestations of SSSS and BI in pyogenic infections of the skin. A variety of predisposing humans (Wiley and Rogolsky, 1977) ETA and ETB. Five factors may lead to more serious infections such as percent of clinical S. aureus isolates produce either ETA, conjunctivitis, pneumonia, septicemia, osteomyelitis, ETB or both toxins (Piemont et al, 1984) and there are septic arthritis, empyema, meningitis, pericarditis or reported geographic differences in the prevalence of the endocarditis. Diseases caused by S. aureus can be the particular toxins that are expressed. In North America, result of direct tissue invasion or due to the action of a Europe and Africa ETA is the predominant ET (Adesiyun variety of exotoxins released by the bacteria (Iandolo, et al, 1991; Ladhani, 2001), in contrast ETB has been 1989; Marrack and Kappler, 1990). S. aureus strains reported to be more common in Japan (Kondo et al, capable of causing disease express a wide variety of 1975). These toxins exhibit exquisite species specificity, virulence factors including exported toxins (exotoxins), being active in humans, mice, monkeys and hamsters The production of this issue of Progress in Dermatology has been underwritten by Galderma Laboratories, L.P. ©2003 Dermatology Foundation, 1560 Sherman Avenue, Evanston, Illinois 60201 1070 122 : 5 MAY 2004 STAPHYLOCOCCUS AUREUS EXFOLIATIVE TOXINS 1071 but not in rats, rabbits, dogs, hedgehogs, voles, guinea exfoliative toxins made by S. hyicus, (ShETA, ShETB pigs, chickens or frogs (Bailey et al, 1995; Elias et al, and ShETC) have also been identified and partially 1975; Ladhani et al, 1999). characterized (Anderson, 1998). These toxins have been associated with comparable skin diseases in different Both ETA and ETB have been cloned and their resul- animal populations but are likewise not associated with tant protein products characterized (Lee et al, 1987; disease in humans. O’Toole and Foster, 1987). The primary human active ETs, ETA and ETB, share significant amino acid identity The ETs, like most staphylococcal proteins associat- with each other and have similar biophysical properties ed with virulence, are encoded on mobile genetic (Bailey et al, 1980; Lee et al, 1987; O’Toole and Foster, elements (Novick, 2003) allowing for horizontal transfer 1987). A comparison of these toxins is shown in Table 1. of these virulence factors. The gene encoding ETA is ETA is a very stable protein that is resistant to extreme located on the bacterial chromosome within a 43 kb heat while ETB is heat sensitive. Both ETA and ETB temperate phage, ␾ETA (Yamaguchi et al, 2000), that share amino acid identity with staphylococcal V8 was recently shown to be capable of transducing a toxin protease (glutamyl endopeptidase I), a well character- negative S. aureus strain to positive. ETB is encoded on ized general serine protease of S. aureus (26% with ETA approximately 38.2-38.5 kb plasmids (Lee et al, 1987; and 31% with ETB). Most significantly, this identity Yamaguchi et al, 2001). ETD was identified within a includes the key amino acid residues of the V8 protease pathogenicity island which also encodes EDIN-B active site, serine-histidine-aspartate. This catalytic triad (Yamaguchi et al, 2002). Pathogenicity islands are is highly conserved and forms the active site of trypsin- varied sized segments of potentially mobile DNA that like serine proteases (Dancer et al, 1990). The X-ray encode virulence associated genes (Kaper and Hacker, crystal structures of both of these toxins have been 1999). These islands have been described for numerous determined (Cavarelli et al, 1997; Papageorgiou et al, types of bacteria and at least three different types of 1999; Vath et al, 1999; Vath et al, 1997). These three- pathogenicity islands have been reported in staphylo- dimensional structures show marked similarity with each coccal species (Kuroda et al, 2001). Also like most other and V8 protease demonstrating that the ETs are staphylococcal virulence factors, the ETs are regulated members of the trypsin-like serine protease family, but by the staphylococcal accessory gene regulator locus, do have some significant differences at the amino- and agr locus (Ji et al, 1995; Novick, 2003). This locus carboxyl-termini. encodes a two-component regulatory system that coordi- nates the expression of specific virulence factors not Recently a new potential human active exfoliative required for bacterial viability, including the exotoxins. toxin, ETD, was identified from an isolate of S. aureus The ETs have a strong association with a particular agr taken from a wound site. It was initially identified as an group, agr group IV, (Jarraud et al, 2000) but the clinical open reading frame which had significant homology to significance of this association remains to be estab- the known ETs (Yamaguchi et al, 2002) but has also lished. been associated with a clinical isolate from a patient with BI (Yamaguchi et al, 2002; Yamaguchi et al, 2002). ETD expressed as a recombinant protein product demon- Clincal conditions caused by the exfoliative strated specific protease activity in the neonatal mouse toxin producing S. aureus. model and exhibits cleavage of recombinant mouse or Staphylococcal scalded skin syndrome and human Dsg1 which is indistinguishable from that of ETA Bullous impetigo. Staphylococcal scalded skin by Western blot analysis (Hanakawa et al, 2002). It was syndrome (SSSS) is an exfoliative dermatitis mediated further shown to be serologically distinct from ETA and by infection with S. aureus capable of producing one or ETB. A fourth potential human active ET produced from both of the exfoliative toxins ETA or ETB. This condition S. aureus, ETC, was isolated from a horse infection and is well described and discussed in several recent was shown to have activity in the neonatal mouse model reviews (Ladhani, 2001; Ladhani and Evans, 1998; (Sato et al, 1994); however, it has not been associated Prevost et al, 2003). It is typically a condition of infants with human disease. The clinical significance of either and young children, although it may also affect adults ETD or ETC has not been established. Other similar (Cribier et al, 1994; Gemmell, 1995). SSSS is characterized by

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