Pyrogenic Exotoxins And Superantigens

Pyrogenic exotoxins of group A streptococci [streptococcal pyrogenic exotoxin (SPE)] and enterotoxins of S. aureus [Staphylococcus enterotoxin (SE)] comprise a group of structurally and functionally related toxins that activate T-cells by a unique mechanism (40,41). The SEs are known to cause staphylococcal food

Lipid A

FIGURE 2 Chemical structures of s. aureus peptidoglycan (PG) and enterobacteriaceae lipid A. Similar structures in PG and lipid A are indicated by brackets. Source: From Ref. 29.

poisoning (enterotoxins) and toxic shock-like syndrome. The streptococcal exotoxins cause the syndrome of scarlet fever and toxic shock-like syndrome as well. These proteins are close in size and homology at approximately 230 amino acids long [toxic shock syndrome toxin-1 (TSST-1) is 194] and are highly heat and protease resistant and, therefore, (in the case of food poisoning) are capable of inducing diarrhea and vomiting via the release of histamines from gut-associated mast cells and may also release inflammatory mediators (cytokines) (42). The pyrogenic exo-toxic SAg also elicit strong inflammatory cytokine host responses and enhance susceptibility to endotoxin shock (42).

According to Kotb (3), most of the "secreted pyrogenic superantigens are globular proteins that range from 20 to 30 kDa in size and, with few exceptions, many have obvious sequence homology." Though the pyrogenic exotoxic SAg differ widely from SAg arising from non-Staphylococcus sources, (mouse mammary tumor virus, Mycoplasm arthriditis, streptococcal M proteins), nevertheless, they apparently share some specific regions of sequence homology. A given structural feature predictive of superantigenicity has not been identified, but it has been postulated that SAg may share conformational features, allowing them to interact broadly with T-cell receptors (TLRs) and major histocompatibility complex (MHC)-II molecules (3). Here is an apparent commonality between SAg and LPS, that is, specific conformational requirements to fit (a) specific receptor(s).

Such biochemical conformations separate toxic LPS from nontoxic forms and common exotoxins from SAg.

Both Staphylococcus (staph TSS) and Streptococcus (strep TSS) derived TSSs have been identified. staph TSS manifests itself in high fever, rash, hypotension, and potentially multiple organ failure. Most menstrual Staph TSS illness is associated with strains of S. aureus that produce the superantigen TSST-1. The term "toxic shock syndrome" was coined and considered a specific affliction in 1978, when it was associated with high absorbency tampons, but today only about half of the staph TSS incidents are said to be menstrually related (43).

Strep TSS and invasive group A streptococcal infections are more often associated with disseminated infections, severe pain, invasion of tissues, and bacteremia (as opposed to dissemination of the exotoxin alone as in staph TSS). The speed and severity of certain streptococcal group A infections has lead to their recent description as "flesh-eating bacteria" (40).

The minority of gram-positive bacteria that do produce exotoxins can be exceedingly pyrogenic, including those arising from S. aureus (enterotoxins) and S. pyogenes (exotoxins). The Staph enterotoxins derive their name from their association with gastrointestinal illness (42). The toxins are low molecular weight (20-30 kDa) proteins and include TSST-1 and SPE-A, SPE-B, and SPE-C (43). SPE-A and SPE-C have been implicated in streptococcal TSS (44). Some of the toxins are structurally related and have been called "SAg" due to their potent and indiscriminant activation of T-cells, which in turn results in the massive release of cytokines and consequent disease pathology, such as TSS. SAg also originate in microbes other than Staphylococcus and Streptococcus, including Mycoplasma species, Pseudomonas aeruginosa, Yersinia pseudotuberculosis and Y. enterocolitica (45), and Clostridium perfringens (3). Certain viruses [Rabies, EBV, MMTV, CMV (46)] and Mycoplasma lipoproteins (22) have also been classified as SAg also that are structurally different from the Staphylococcus and Streptococcus exotoxins. Ulrich (47) states that the SAgs of S. aureus and group A Strep have common genetic origins, and also underscores the "mobile nature of their (SAgs) genetic elements."

The unique property of SAgs is their ability to interact with a large number of T-cells that share specific sequences within the variable region of the T-cell receptor (TCR). Normal antigens bind only a small number of T-cells and do not recognize the specific-like sequences (invariant regions) in the otherwise variable region. See Figure 3 for a diagram of proposed SAg structure and function. By their indiscriminant attachment mechanism, SAgs connect antigen-presenting cells (APC) and T-cells, thereby escaping the need to be processed by APC, a rate-limiting step in antigen processing (43). Conventional antigens are processed into small peptides in lysosomal compartments of APCs where they complex with MHC molecules. This results in the aberrant proliferation of T-cells with specific (Vb) subsets (42). In contrast to normal antigens in which binding to MHC is determined by five variable regions of TCR: Vb, Db, Jb, Vo, and Jo, the interaction of SAg is dictated primarily by the Vb area. Therefore, the contrast in ability to combine with MHC (APC) and TCR is stark (3).

1. Antigens: one cell in 104 to 106 T-cells (0.0001-0.000001%).

The end result of SAg host interaction is the stimulation of large numbers of T-cells, which in turn trigger the initiation of defensive cellular events including cytokine gene expression. It is relevant to remember the different general routes

FIGURE 3 Bridging of T-cells and antigen-presenting cells: a schematic model of superantigen (SAg) interaction with T-cell receptor and class II molecules. Ag is the normal antigen-binding site whereas SAg is the superantigen-binding site on the variable region that this particular SAg is specific for. Abbreviations: Ag, antigen; APC, antigen-presenting cells; MHC, major histocompatibility complex; SAg, superantigen. TCR, T-cell receptor; Source: From Ref. 3.

FIGURE 3 Bridging of T-cells and antigen-presenting cells: a schematic model of superantigen (SAg) interaction with T-cell receptor and class II molecules. Ag is the normal antigen-binding site whereas SAg is the superantigen-binding site on the variable region that this particular SAg is specific for. Abbreviations: Ag, antigen; APC, antigen-presenting cells; MHC, major histocompatibility complex; SAg, superantigen. TCR, T-cell receptor; Source: From Ref. 3.

of invasion associated with gram-positive versus gram-negative organisms. As noted by Sriskandan and Cohen (28), gram-negatives typically arise from within (i.e., via parenteral, gastrointestinal, humoral, urologic entry) whereas grampositives typically arise from without (i.e., via invasive medical procedures such as catheters, intravenous tubes, food borne, etc.), and often from a locus of infection (skin, wound, muscle injury). Gram-positive organisms more often have large antiphagocytic capsules that are not susceptible to the lytic action of complement. In host systems, they may multiply rapidly and cause bacteremia if they do gain entry systemically.

Kotb (3) lists three criteria of a protein to be designated as SAg:

1. Reproducible pattern of selective Vfi interaction (i.e., it interacts with a Vb region common to a subpopulation of T-cells)

2. Dependence of the response on APC that express class II molecules

3. Ability to bypass APC complex processing

In addition to Vb interaction, exotoxic pyrogenic SAg also induce inflammatory cytokine production and enhanced susceptibility to endotoxin shock. Although there are structural similarities among many SAg, there has not been a specific structure identified as a predictor of superantigenicity.

The pathogenisis of SAg, as in the case of endotoxin, is mediated by the body's aberrant immune response. Diseases known to be caused by SAg include food poisoning, menstrual and nonmenstrual, staph TSS and strep TSS. Suspect but not proven diseases associated with SAg include a host of diseases including Lyme disease, Kawasaki disease, rheumatoid arthritis, and multiple sclerosis (3). See Tables 2 and 3 for known and suspected human diseases associated with SAg. Most recently, SAg have been associated with a number of autoimmune disorders

TABLE 2 Known and Suspected Human Diseases Associated with Superantigens

Disease Superantigena

Acute diseases Food poisoning Staph TSS Menstrual Nonmenstrual

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