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Identified virulence factors of Staphylococcus: Toxin


α-hemolysin  

Related genes: hly/hla;
Keywords: Toxin; Membrane-damaging; Pore-forming toxin; Beta-barrel pore-forming toxin;
Structure features:
A paradigm for pore-forming toxins that utilize a β-barrel structure for channel formation.
PDB code :7AHL.
Functions:
Forms pores in cell membrane to kill or limit the ability of neutrophils.
Inducing cellular damage that triggers cytokine production.
Mechanism:
Secreted α-hemolysin protomer is a hydrophilic protein of approximately 33 kDa. Once associated with the target cell membrane, seven protomers assemble into a pre-pore complex that subsequently inserts into the membrane to form the channel. The channel is formed by a β-barrel constructed from 14 anti-parallel β-strands, two being donated from each protomer..
Binds the cellular receptor ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) to upregulate ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin.
References:
Inoshima I, et al., 2011. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med. 17(10):1310-1314.


β-hemolysin  

Related genes: hlb;
Keywords: Toxin; Membrane-damaging; Hydrolase;
Functions:
Tissue invasion,.
Mechanism:
Sphingomyelinase, specifically cleaves sphingomyelin into phosphocholine and ceramide.
References:
Dinges MM, et al., 2000. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13(1):16-34.


δ-hemolysin  

Related genes: hld;
Keywords: Toxin; Membrane-damaging; Pore-forming toxin; Alpha-helix pore-forming toxin;
Functions:
Capable of lysing erythrocytes and other mammalian cells, as well as subcellular structures.
Mechanism:
Forms α-helix with hydrophobic and hydrophilic domains on opposite sides and aggregates to form channels channels in the membrane.
References:
Dinges MM, et al., 2000. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13(1):16-34.


γ-hemolysin  

Related genes: hlgA; hlgB; hlgC;
Keywords: Toxin; Membrane-damaging; Pore-forming toxin; Beta-barrel pore-forming toxin; Biocomponent leukocidin;
Characteristics:
Three protein (HlgA, HlgB, HlgC) are virtually identical in sequence to leukocidin component S and F, thus γ-hemolysin may act similarly to leukocidin.
S component: HlgA, HlgC. F component: HlgB.
Structure features:
Leukocidin F (Hlgb): 1LKF.
Functions:
Have a role similar to that of PVL.
References:
Comai M, et al., 2002. Protein engineering modulates the transport properties and ion selectivity of the pores formed by staphylococcal gamma-haemolysins in lipid membranes. Mol Microbiol 44(5):1251-1267.


Exfoliative toxin  

Related genes: eta; etb;
Keywords: Toxin; Serine protease;
Characteristics:
Four antigenically distinct exfoliative toxins are identified so far: exfoliative toxin A (ETA) and B (ETB) are responsible for most human staphylococcal scalded skin syndrome. ETC was isolated from a horse with skin infection. Recently, ETD was identified as a new potential human active exofoliative toxin.
Both ETA and ETB share amino acid identity with staphylococcal V8 serine protease.
ETA is a very stable protein that is resistant to extreme heat while ETB is heat sensitive.
Structure features:
PDB code for ETA: 1DUA.
PDB code for ETB: 1DT2.
Functions:
Primarily responsible for the skin manifestation of staphylococcal scalded skin syndrome and bullous impetigo.
Mechanism:
Acting as serine protease: target is Dsg-1 (desmoglein-1), produced only in the skin. The role of Dsg-1 is to maintain keratinocyte cell-cell adhesion. Cleavage of Dsg-1 would lead to separation of skin keratinocytes, a result that would lead to the sort of separation of layers of epidermal tissue seen in scalded skin syndrome and bullous impetigo.
May also act as potential superantigens.
References:
Sato H, et al., 1994. A new type of staphylococcal exfoliative toxin from a Staphylococcus aureus strain isolated from a horse with phlegmon. Infect. Immun. 62(9):3780-3785.
Amagai M, et al., 2000. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat. Med. 6(11):1275-1277.
Amagai M, et al., 2002. Staphylococcal exfoliative toxin B specifically cleaves desmoglein 1. J. Invest. Dermatol. 118(5):845-850.
Hanakawa Y, et al., 2002. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. J. Clin. Invest. 110(1):53-60.
Yamaguchi T, et al., 2002. Identification of the Staphylococcus aureus etd pathogenicity island which encodes a novel exfoliative toxin, ETD, and EDIN-B. Infect. Immun. 70(10):5835-5845.
Ladhani S, 2003. Understanding the mechanism of action of the exfoliative toxins of Staphylococcus aureus. FEMS Immunol. Med. Microbiol. 39(2):181-189.


PVL (Panton-Valentine leukocidin)  

Related genes: lukF-PV; lukS-PV;
Keywords: Toxin; Membrane-damaging; Pore-forming toxin; Beta-barrel pore-forming toxin; Biocomponent leukocidin;
Characteristics:
PVL, together with γ-hemolysin and other leukocidins such as LukE-LukD, belongs to the family of bicomponent synergohymenotropic toxins.
Pore-forming toxin rich in β-sheet structures.
Structure features:
LukF-PV component: the stem domain is folded into three antiparallel β-strand in the water-soluble form and refold into a transmembrane β-hairpin during pore formation.
PDB code: 1PVL.
Functions:
Induce cell activation linked to a Ca2+ influx, and pore formation as two consecutive and independently inhibitable events.
References:
Loffler B, et al., 2010. Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog 6(1):e1000715-e10007.


SE (staphylococcal enterotoxin)  

Related genes: sea; seb; sec1; sec3; sed; see; seh; selk; selq;
Keywords: Toxin; Membrane-acting; Superantigen;
Characteristics:
Constitutes a family of eight single-chain polypeptides (26-28kDa, 228-239 amino acid residues) with a typical disulfide loop.
Divided into two groups based on amino acid sequence homology: the first group consists of SEA,SEE, SED and SEH, and the second group including SEB, SEC, SEG.
Structure features:
Staphylococcal Enterotoxin A: 1ESF.
Staphylococcal Enterotoxin B: 3SEB.
Staphylococcal Enterotoxin C2: 1STE.
Staphylococcal Enterotoxin C3: 1CK1.
Figures:
Representation of T cell activation by a conventional peptide antigen or by a superantigenic toxin;


Functions:
Responsible for the symptoms of food poisoning.
References:
Dinges MM, et al., 2000. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13(1):16-34.
Papageorgiou AC, Acharya KR, 2000. Microbial superantigens: from structure to function. Trends Microbiol. 8(8):369-375.
McCormick JK, et al., 2001. Toxic shock syndrome and bacterial superantigens: an update. Annu. Rev. Microbiol. 55:77-104.


TSST-1 (Toxic shock syndrome toxin-1)  

Related genes: tsst-1;
Keywords: Toxin; Membrane-acting; Superantigen;
Characteristics:
Encoded by tst present on staphylococcal pathogenicity island 1 (SaPI1).
Produced by approximately 20% of natural isolates.
Lacks disulfide loop and shows no significant homology to any of the other streptococcal and staphylococcal superantigens.
Structure features:
PDB code: 1QIL.
Functions:
Responsible for the symptoms of toxic shock syndrome.
Mechanism:
Acting as superantigens: stimulating T cells by cross-linking the variable part of the β-chain of the T-cell receptor with major histocompatibility complex class I molecules on accessory or target T cells outside the peptide-binding groove area. This will result in a nonspecific activation of a large proportion of T cells.
References:
Kim J, et al., 1994. Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. Science 266(5192):1870-1874.
Prasad GS, et al., 1993. Structure of toxic shock syndrome toxin 1. Biochemistry. 32(50):13761-13766.
Miethke T, et al., 1993. Pathogenesis of the toxic shock syndrome: T cell mediated lethal shock caused by the superantigen TSST-1. Eur. J. Immunol. 23(7):1494-1500.
Prasad GS, et al., 1997. Refined structures of three crystal forms of toxic shock syndrome toxin-1 and of a tetramutant with reduced activity. Protein Sci. 6(6):1220-1227.
Lindsay JA, et al., 1998. The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus. Mol. Microbiol. 29(2):527-543.
Dinges MM, et al., 2000. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13(1):16-34.








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