Streptococcal pyrogenic exotoxin

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Cartoon representation of the molecular structure of SpeA1. PDB 1fnv EBI.jpg
Cartoon representation of the molecular structure of SpeA1.

Streptococcal pyrogenic exotoxins also known as erythrogenic toxins, are exotoxins secreted by strains of the bacterial species Streptococcus pyogenes . [1] [2] SpeA and speC are superantigens, which induce inflammation by nonspecifically activating T cells and stimulating the production of inflammatory cytokines. [3] SpeB, the most abundant streptococcal extracellular protein, is a cysteine protease. [4] [5] Pyrogenic exotoxins are implicated as the causative agent of scarlet fever and streptococcal toxic shock syndrome. [2] There is no consensus on the exact number of pyrogenic exotoxins. Serotypes A-C[ clarification needed ] are the most extensively studied and recognized by all sources, but others note up to thirteen distinct types, categorizing speF through speM as additional superantigens. [1] [2] [6] [7] Erythrogenic toxins are known to damage the plasma membranes of blood capillaries under the skin and produce a red skin rash (characteristic of scarlet fever). [8] Past studies have shown that multiple variants of erythrogenic toxins may be produced, depending on the strain of S. pyogenes in question. Some strains may not produce a detectable toxin at all. [9] Bacteriophage T12 infection of S. pyogenes enables the production of speA, and increases virulence. [10]

Contents

History

Discovery and nomenclature

SpeB was identified in 1919 as an ectoenzyme secreted by certain strains of streptococci. [11] It was originally studied as two separate toxins, streptococcal pyrogenic exotoxin B and streptococcal cysteine proteinase, until it was shown that both proteins were encoded by the speB gene and that the attributed pyrogenic activities were due to contamination by SpeA and SpeC. [12]

Pyrogenic, in streptococcal pyrogenic exotoxin, means "causes fever." [13] Erythrogenic refers to the typical red rash of scarlet fever. In older literature, these toxins are also referred to as scarlatina toxins or scarlet fever toxins due to their role as the causative agents of the disease. [2]

SpeB is known as streptococcal pyrogenic exotoxin B, streptopain and streptococcal cysteine proteinase as a result of its original misidentification as two separate toxins, and is neither an exotoxin nor pyrogenic. [12]

Structure

Location of genes

The speB and speJ genes are located in the core bacterial chromosome of all strains of S. pyogenes. [3] [14] However, despite its presence and high levels of conservation in the nucleotide sequence, 25-40% of these strains do not express the SpeB toxin in significant amounts. [14]

In contrast, speA, speC and speH-M are encoded by bacteriophages. [3] [15]

There is a lack of consensus over the location of the speG gene, which has been attributed to both the core chromosome and lysogenic phages. [1]

Protein structure

Structure of SpeB. PDB 1pvj EBI.jpg
Structure of SpeB.

SpeB is a 28 kDa protein with three major forms, mSpeB1, mSpeB2 and mSpeB3, which are categorized by variations the primary amino acid sequence. [4] Three amino acids, C192, H340, and W357, are vital for enzymatic activity in all variants. [11] The toxin contains a canonical papain-like domain, and mSpeB2 has an additional human integrin binding domain. [4] [11]

Structure of SpeA1. PDB 1b1z EBI.jpg
Structure of SpeA1.

All superantigenic streptococcal pyrogenic exotoxins contain two major conserved protein domains that are linked by an α-helix, which consist of an amino-terminal oligosoccharide/oligonucleotide binding fold and a carboxy-terminal β-grasp domain, as well as dodecapeptide binding region. SpeA also has a cystine loop, a low-affinity α-chain MHC II binding site, and the Vβ-TCR binding site. SpeC, SpeG, SpeH and SpeJ contains a Zn2+-dependent high β-chain MHC II binding site in addition to the low affinity site present in SpeA, and lacks the cystine loop. SpeH also has an additional α3-β8 loop that mediates the specificity of the toxin's Vβ-TCR binding site. [2]

Processing and regulation

The speB gene encodes for an amino acid sequence that becomes the 40 kDa zymogen, known as SpeBz, after cleavage of the signal sequence. [11] SpeBz undergoes autocatalysis through at least eight intermediates to create the 28 kDa SpeBm. Finally cystine-192 and histidine-340 form a catalytic dyad. [4] [5] Each step is tightly regulated by multiple factors, allowing sophisticated temporal expression of the mature proteinase. [11]

Mechanisms of action

T-cell dependent b-cell activation, showing TH2-cell (left) B-cell (right) and several interaction molecules. T-cell dependent b-cell act.jpg
T-cell dependent b-cell activation, showing TH2-cell (left) B-cell (right) and several interaction molecules.
T-cell receptor. 2215 Alpha-Beta T Cell Receptor.jpg
T-cell receptor.

SpeA and speC

SpeA and SpeC bind to MHC Class II molecules, are presented to T cells, and bind to the variable region of the beta chain of T-cell receptors (TCRs). [3] Once activated, the T cells release pro-inflammatory cytokines and chemokines. [1] The interactions with TCRs are characterized by low affinities and fast dissociation, allowing the toxin to activate multiple T cells in succession. [7] The lack of specificity allow the activation of up to 50% of the T cells in the body. [6]

SpeB

SpeB cleaves degrades multiple proteins through hydrolysis, including cytokines, extracellular matrix proteins and immunoglobulin. [12] It requires three amino acids before the cleavage site, known as P1, P2 and P3. Of these, SpeB has a preference for hydrophobic P2 and positively charged P1 residues, with greater importance of the P2 amino acid. [5] [11]

Roles in virulence, pathogenesis and infection

SpeB

Streptococcal cysteine proteinase has roles in immune evasion and apoptosis, as well as potential influence on bacterial internalization. There is contradictory evidence regarding the effect of SpeB on virulence. Some studies have reported increased protease levels in strains that cause scarlet fever in comparison to those associated with streptococcal toxic shock syndrome, while others show decreased expression in more virulent strains. [4]

SpeB degrades immunoglobulins and cytokines, as well as through cleavage of C3b, inhibiting recruitment of phagocytic cells and the complement activation pathway. [5] This results in decreased inflammation and neutrophil levels around the site of infection, preventing clearance and through phagocytosis and promoting the survival of S. pyogenes. [4] [5]

The toxin also induces apoptosis in host cells after GAS internalization. Evidence suggests that this may take place through extrinsic and intrinsic caspase pathways. The receptor-binding pathway and Fas-mediated apoptotic signaling pathway have been implicated in this process. [4] The induction of apoptosis results in necrotizing fasciitis.

Related Research Articles

<i>Streptococcus</i> Genus of bacteria

Streptococcus is a genus of gram-positive coccus or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales, in the phylum Bacillota. Cell division in streptococci occurs along a single axis, so as they grow, they tend to form pairs or chains that may appear bent or twisted. This differs from staphylococci, which divide along multiple axes, thereby generating irregular, grape-like clusters of cells. Most streptococci are oxidase-negative and catalase-negative, and many are facultative anaerobes.

<i>Streptococcus pyogenes</i> Species of bacterium

Streptococcus pyogenes is a species of Gram-positive, aerotolerant bacteria in the genus Streptococcus. These bacteria are extracellular, and made up of non-motile and non-sporing cocci that tend to link in chains. They are clinically important for humans, as they are an infrequent, but usually pathogenic, part of the skin microbiota that can cause Group A streptococcal infection. S. pyogenes is the predominant species harboring the Lancefield group A antigen, and is often called group A Streptococcus (GAS). However, both Streptococcus dysgalactiae and the Streptococcus anginosus group can possess group A antigen as well. Group A streptococci, when grown on blood agar, typically produce small (2–3 mm) zones of beta-hemolysis, a complete destruction of red blood cells. The name group A (beta-hemolytic) Streptococcus (GABHS) is thus also used.

<span class="mw-page-title-main">Scarlet fever</span> Infectious disease caused by Streptococcus pyogenes

Scarlet fever, also known as scarlatina, is an infectious disease caused by Streptococcus pyogenes, a Group A streptococcus (GAS). The infection is a type of Group A streptococcal infection. It most commonly affects children between five and 15 years of age. The signs and symptoms include a sore throat, fever, headache, swollen lymph nodes, and a characteristic rash. The face is flushed and the rash is red and blanching. It typically feels like sandpaper and the tongue may be red and bumpy. The rash occurs as a result of capillary damage by exotoxins produced by S.pyogenes. On darker-pigmented skin the rash may be hard to discern.

<span class="mw-page-title-main">Toxic shock syndrome</span> Medical condition

Toxic shock syndrome (TSS) is a condition caused by bacterial toxins. Symptoms may include fever, rash, skin peeling, and low blood pressure. There may also be symptoms related to the specific underlying infection such as mastitis, osteomyelitis, necrotising fasciitis, or pneumonia.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

<span class="mw-page-title-main">Enterotoxin</span> Toxin from a microorganism affecting the intestines

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. They can be chromosomally or plasmid encoded. They are heat labile (>60⁰), of low molecular weight and water-soluble. Enterotoxins are frequently cytotoxic and kill cells by altering the apical membrane permeability of the mucosal (epithelial) cells of the intestinal wall. They are mostly pore-forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.

<span class="mw-page-title-main">Lysogenic cycle</span> Process of virus reproduction

Lysogeny, or the lysogenic cycle, is one of two cycles of viral reproduction. Lysogeny is characterized by integration of the bacteriophage nucleic acid into the host bacterium's genome or formation of a circular replicon in the bacterial cytoplasm. In this condition the bacterium continues to live and reproduce normally, while the bacteriophage lies in a dormant state in the host cell. The genetic material of the bacteriophage, called a prophage, can be transmitted to daughter cells at each subsequent cell division, and later events can release it, causing proliferation of new phages via the lytic cycle. Lysogenic cycles can also occur in eukaryotes, although the method of DNA incorporation is not fully understood. For instance the AIDS viruses can either infect humans lytically, or lay dormant (lysogenic) as part of the infected cells' genome, keeping the ability to return to lysis at a later time. The rest of this article is about lysogeny in bacterial hosts.

<i>Yersinia pseudotuberculosis</i> Species of bacterium

Yersinia pseudotuberculosis is a Gram-negative bacterium that causes Far East scarlet-like fever in humans, who occasionally get infected zoonotically, most often through the food-borne route. Animals are also infected by Y. pseudotuberculosis. The bacterium is urease positive.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

<span class="mw-page-title-main">Diphtheria toxin</span> Exotoxin

Diphtheria toxin is an exotoxin secreted mainly by Corynebacterium diphtheriae but also by Corynebacterium ulcerans and Corynebacterium pseudotuberculosis. the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophage called corynephage β. The toxin causes the disease in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.

<span class="mw-page-title-main">Lysin</span>

Lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages in order to cleave the host's cell wall during the final stage of the lytic cycle. Lysins are highly evolved enzymes that are able to target one of the five bonds in peptidoglycan (murein), the main component of bacterial cell walls, which allows the release of progeny virions from the lysed cell. Cell-wall-containing Archaea are also lysed by specialized pseudomurein-cleaving lysins, while most archaeal viruses employ alternative mechanisms. Similarly, not all bacteriophages synthesize lysins: some small single-stranded DNA and RNA phages produce membrane proteins that activate the host's autolytic mechanisms such as autolysins.

<span class="mw-page-title-main">Toxic shock syndrome toxin-1</span>

Toxic shock syndrome toxin-1 (TSST-1) is a superantigen with a size of 22 kDa produced by 5 to 25% of Staphylococcus aureus isolates. It causes toxic shock syndrome (TSS) by stimulating the release of large amounts of interleukin-1, interleukin-2 and tumour necrosis factor. In general, the toxin is not produced by bacteria growing in the blood; rather, it is produced at the local site of an infection, and then enters the blood stream.

Streptolysins are two hemolytic exotoxins from Streptococcus. Types include streptolysin O, which is oxygen-labile, and streptolysin S, which is oxygen-stable.

<i>Streptococcus dysgalactiae</i> Species of bacterium

Streptococcus dysgalactiae is a gram positive, beta-haemolytic, coccal bacterium belonging to the family Streptococcaceae. It is capable of infecting both humans and animals, but is most frequently encountered as a commensal of the alimentary tract, genital tract, or less commonly, as a part of the skin flora. The clinical manifestations in human disease range from superficial skin-infections and tonsillitis, to severe necrotising fasciitis and bacteraemia. The incidence of invasive disease has been reported to be rising. Several different animal species are susceptible to infection by S. dysgalactiae, but bovine mastitis and infectious arthritis in lambs have been most frequently reported.

A corynebacteriophage is a DNA-containing bacteriophage specific for bacteria of genus Corynebacterium as its host.

<span class="mw-page-title-main">Enterotoxin type B</span>

In the field of molecular biology, enterotoxin type B, also known as Staphylococcal enterotoxin B (SEB), is an enterotoxin produced by the gram-positive bacteria Staphylococcus aureus. It is a common cause of food poisoning, with severe diarrhea, nausea and intestinal cramping often starting within a few hours of ingestion. Being quite stable, the toxin may remain active even after the contaminating bacteria are killed. It can withstand boiling at 100 °C for a few minutes. Gastroenteritis occurs because SEB is a superantigen, causing the immune system to release a large amount of cytokines that lead to significant inflammation.

Bacteriophage T12 is a bacteriophage that infects Streptococcus pyogenes bacteria. It is a proposed species of the family Siphoviridae in the order Caudovirales also known as tailed viruses. It converts a harmless strain of bacteria into a virulent strain. It carries the speA gene which codes for erythrogenic toxin A. speA is also known as streptococcal pyogenic exotoxin A, scarlet fever toxin A, or even scarlatinal toxin. Note that the name of the gene "speA" is italicized; the name of the toxin "speA" is not italicized. Erythrogenic toxin A converts a harmless, non-virulent strain of Streptococcus pyogenes to a virulent strain through lysogeny, a life cycle which is characterized by the ability of the genome to become a part of the host cell and be stably maintained there for generations. Phages with a lysogenic life cycle are also called temperate phages. Bacteriophage T12, proposed member of family Siphoviridae including related speA-carrying bacteriophages, is also a prototypic phage for all the speA-carrying phages of Streptococcus pyogenes, meaning that its genome is the prototype for the genomes of all such phages of S. pyogenes. It is the main suspect as the cause of scarlet fever, an infectious disease that affects small children.

RopB transcriptional regulator, also known as RopB/Rgg transcriptional regulator is a transcriptional regulator protein that regulates expression of the extracellularly secreted cysteine protease streptococcal pyrogenic exotoxin B (speB) [See Also: erythrogenic toxins] which is an important virulence factor of Streptococcus pyogenes and is responsible for the dissemination of a host of infectious diseases including strep throat, impetigo, streptococcal toxic shock syndrome, necrotizing fasciitis, and scarlet fever. Functional studies suggest that the ropB multigene regulon is responsible for not only global regulation of virulence but also a wide range of functions from stress response, metabolic function, and two-component signaling. Structural studies implicate ropB's regulatory action being reliant on a complex interaction involving quorum sensing with the leaderless peptide signal speB-inducing peptide (SIP) acting in conjunction with a pH sensitive histidine switch.

Shiranee Sriskandan is a British academic who is Professor of Infectious Diseases at Imperial College London and Honorary Consultant at Hammersmith Hospital. Her research considers how Gram-positive bacteria cause disease, with a particular focus on the bacteria Streptococcus pyogenes.

References

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  5. 1 2 3 4 5 Nelson, Daniel C.; Garbe, Julia; Collin, Mattias (2011). "Cysteine proteinase SpeB from Streptococcus pyogenes – a potent modifier of immunologically important host and bacterial proteins". Biological Chemistry. 392 (12): 1077–88. doi: 10.1515/bc.2011.208 . PMID   22050223. S2CID   207441558.
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  8. ↑ Tortora, Gerard; Funke, Berdell; Case, Christine (2013). Microbiology (11th ed.). Pearson. p. 439.
  9. ↑ Knöll H, Srámek J, Vrbová K, Gerlach D, Reichardt W, Köhler W (December 1991). "Scarlet fever and types of erythrogenic toxins produced by the infecting streptococcal strains". Zentralbl Bakteriol. 276 (1): 94–106. doi:10.1016/s0934-8840(11)80223-9. PMID   1789905.
  10. ↑ McShan, WM; Tang, YF; Ferretti, JJ (1997). "Bacteriophage T12 of Streptococcus pyogenes integrates into the gene encoding a serine tRNA". Molecular Microbiology. 23 (4): 719–28. doi: 10.1046/j.1365-2958.1997.2591616.x . PMID   9157243.
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  13. ↑ "Pyrogen (definition)". The Free Dictionary.
  14. 1 2 Chiang-Ni, Chuan; Wu, Jiunn-Jong (2008). "Effects of Streptococcal Pyrogenic Exotoxin B on Pathogenesis of Streptococcus pyogenes". Journal of the Formosan Medical Association. 107 (9): 677–685. doi: 10.1016/s0929-6646(08)60112-6 . PMID   18796357.
  15. ↑ Boyd, E. Fidelma (2012). "Bacteriophage-Encoded Bacterial Virulence Factors and Phage–Pathogenicity Island Interactions". In Szybalski, Małgorzata Łobocka and Wacław T. (ed.). Chapter 4 - Bacteriophage-Encoded Bacterial Virulence Factors and Phage–Pathogenicity Island Interactions. pp. 91–118. doi:10.1016/b978-0-12-394621-8.00014-5. ISBN   9780123946218. PMID   22420852.{{cite book}}: |journal= ignored (help)
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