Molecular Characteristics and Pathogenicity of Staphylococcus aureus Exotoxins

Abstract

Staphylococcus aureus stands as one of the most pervasive pathogens given its morbidity and mortality worldwide due to its roles as an infectious agent that causes a wide variety of diseases ranging from moderately severe skin infections to fatal pneumonia and sepsis. S. aureus produces a variety of exotoxins that serve as important virulence factors in S. aureus-related infectious diseases and food poisoning in both humans and animals. For example, staphylococcal enterotoxins (SEs) produced by S. aureus induce staphylococcal foodborne poisoning; toxic shock syndrome toxin-1 (TSST-1), as a typical superantigen, induces toxic shock syndrome; hemolysins induce cell damage in erythrocytes and leukocytes; and exfoliative toxin induces staphylococcal skin scalded syndrome. Recently, Panton-Valentine leucocidin, a cytotoxin produced by community-associated methicillin-resistant S. aureus (CA-MRSA), has been reported, and new types of SEs and staphylococcal enterotoxin-like toxins (SEls) were discovered and reported successively. This review addresses the progress of and novel insights into the molecular structure, biological activities, and pathogenicity of both the classic and the newly identified exotoxins produced by S. aureus.

Keywords: Panton–Valentine leucocidin; exfoliative toxin; hemolysin; membrane-damaging toxin; staphylococcal enterotoxin; superantigen.

Figure 1

SE and SEl genes carried by SaPIs, υSa genomic islands, prophages, and plasmids based on sequencing data and modified from Novick and Subedi [23], Thomas et al. [14], Collery et al. [26], and Hu et al. [1]. different color of arrows means different genetic elements.

Figure 2

Molecular structures of SEs and SEls. SEs and SEls are single-chain proteins with molecular weights ranging from 19 to 30 kDa. The three-dimensional structures of SEs and SEls show very similar conformations wherein the canonical structure consists of one A domain, one B domain, and one α-helix that spans the center of the structure and connects the A and B domains.

Figure 3

Biological activities of SEs and SEls. A. Emetic activity of SEs. Submucosal mast cells in the gastrointestinal tract are one of the target cells of SEs, and the serotonin released from mast cells and/or neuron cells plays an important role in SE-induced emesis and food poisoning. B. Superantigenic activity of SEs and SEls. Superantigens (SAgs), unlike conventional antigens, bypass normal processing by APCs, induce a large proportion of T-cells to proliferate, and subsequently stimulate a massive cytokine release that mediates the toxic effects of the toxins. C. Ability to cause infection diseases in different species using various cell pathways.

Figure 4

The hemolytic mechanism of α-hemolysin. (1) α-Hemolysin is a water-soluble monomer. (2) α-Hemolysin binds to the transmembrane protein ADAM10 that is a hemolysin receptor. (3) The toxin then oligomerizes at the plasma membrane to form heptamers and form pre-pores and (4) finally forms transmembrane channels.

Figure 5

Mechanism of action of leukotoxin. (A) The bicomponent leukotoxin, LukAB. (1) LukAB is secreted as dimers. (2) LukAB recognizes the target cell by binding to cell surface receptors, namely, the integrin, CD11b. (3) Upon receptor binding, they dimerize with additional leukocidin dimers to form an octameric pre-pore. (4) The prestem domains of the pre-pore extend to form a β-barrel pore, which eventually destroys the target cell membrane. (B) Bicomponent leukocidins (except LukAB). (1) The leukotoxins are secreted as monomers. (2) The S subunit recognizes the target cell by binding to cell surface receptors that are typically GPCRs. (3) The S subunit dimerizes with the F subunit. (4) These dimers oligomerize at the plasma membrane and a pre-pore appears. (5) Finally, transmembrane channels are formed, thus disrupting the target cell membrane.

Figure 6

Pore-formation mechanism of phenol-soluble modulins (PSMs). (1) PSMs attach the cytoplasmic membrane in a non-specific way. (2) The attachment can lead to membrane disintegration. (3) PSMs aggregate in oligomers and form a short-lived pore.