Toxic shock syndrome toxin-1

Last updated
Toxic shock syndrome toxin-1
3TSS PDB.png
Crystallographic structure of TSST-1
Identifiers
Organism Staphylococcus aureus
Symboltst
PDB 3TSS
RefSeq (Prot) WP_001035596.1
UniProt P06886
Search for
Structures Swiss-model
Domains InterPro

Toxic shock syndrome toxin-1 (TSST-1) is a superantigen with a size of 22 kDa [1] 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.

Contents

Characteristics

Toxic shock syndrome toxin-1 (TSST-1), a prototype superantigen secreted by a Staphylococcus aureus bacterium strain in susceptible hosts, acts on the vascular system by causing inflammation, fever, and shock. [2] The bacterium strain that produces the TSST-1 can be found in any area of the body, but lives mostly in the vagina of infected women. TSST-1 is a bacterial exotoxin found in patients who have developed toxic shock syndrome (TSS), which can be found in menstruating women or any man or child for that matter. [3] One-third of all TSS cases have been found in men. [4] This statistic could possibly be due to surgical wounds or any skin wound. [4] TSST-1 is the cause of 50% of non-menstrual and 100% of all menstrual TSS cases. [5]

Structure

In the nucleotide sequence of TSST-1, there is a 708 base-pair open-reading frame and a Shine-Dalgarno sequence which is seven base pairs downstream from the start site. [6] In the entire nucleotide sequence, only 40 amino acids make up the signal peptide. A single signal peptide consists of a 1 to 3 basic amino acid terminus, a hydrophobic region of 15 residues, a proline (Pro) or glycine (Gly) in the hydrophobic core region, a serine (Ser) or threonine (Thr) amino acid near the carboxyl terminal end of the hydrophobic core, and an alanine (Ala) or glycine (Gly) at the cleavage site. [6] A mature TSST-1 protein has a coding sequence of 585 base pairs. [6] The entire nucleotide sequence was determined by Blomster-Hautamaazg, et al., as well as by other researchers with other experiments. [6] Consisting of a single polypeptide chain, the structure of holotoxin TSST-1 is three-dimensional and consists of an alpha (α) and beta (β) domain. [1] This three-dimensional structure of the TSST-1 protein was determined by purifying the crystals of the protein. [1] The two domains are adjacent from each other and possess unique qualities. Domain A, the larger of the two domains, contains residues 1-17 and 90-194 in TSST-1 and consists of a long alpha (α) helix with residues 125-140 surrounded by a 5-strand beta (β) sheet. [1] [5] Domain B is unique because it contains residues 18-89 in TSST-1 and consists of a (β) barrel made up of 5 β-strands. [1] Crystallography methods show that the internal β-barrel of domain B contains several hydrophobic amino acids and hydrophilic residues on the surface of the domain, which allows TSST-1 to cross mucous surfaces of epithelial cells. [1] Even though TSST-1 consists of several hydrophobic amino acids, this protein is highly soluble in water. [5] TSST-1 is resistant to heat and proteolysis. It has been shown that TSST-1 can be boiled for more than an hour without any presence of denaturation or direct effect on its function. [5]

Production

TSST-1 is a protein encoded by the tst gene, which is part of the mobile genetic element staphylococcal pathogenicity island 1. [1] The toxin is produced in the greatest volumes during the post-exponential phase of growth, which is similar among pyrogenic toxin superantigens, also known as PTSAgs. [1] Oxygen is required in order to produce TSST-1, [7] in addition to the presence of animal protein, low levels of glucose, and temperatures between 37-40 °C (98.6-104 °F). [1] Production is optimal at pH's close to neutral and when magnesium levels are low, [8] and is further amplified by high concentrations of S. aureus, which indicates its importance in establishing infection. [1]

TSST-1 differs from other PTSAgs in that its genetic sequence does not have a homolog with other superantigen sequences. [1] TSST-1 does not have a cysteine loop, which is an important structure in other PTSAgs. [9] TSST-1 is also different from other PTSAgs in its ability to cross mucous membranes, which is why it is an important factor in menstrual TSS. [1] When the protein is translated, it is in a pro-protein form, and can only leave the cell once the signal sequence has been cleaved off. [1] The agr (accessory gene regulator) locus [lower-alpha 1] is one of the key sites of positive regulation for many of the S. aureus genes, including TSST-1. [9] Additionally, alterations in the expression of the genes ssrB and srrAB affect the transcription of TSST-1. [7] Further, high levels of glucose inhibit transcription, since glucose acts as a catabolite repressor. [1]

Mutations

Based on studies of various mutations of the protein it appears that the superantigenic and lethal portions of the protein are separate. [1] One variant in particular, TSST-ovine or TSST-O, was important in determining the regions of biological importance in TSST-1. [12] TSST-O does not cause TSS, and is non-mitogenic, and differs in sequence from TSST-1 in 14 nucleotides, which corresponds to 9 amino acids. [12] Two of these are cleaved off as part of the signal sequence, and are therefore not important in the difference in function observed. [12] From the studies observing the differences in these two proteins, it was discovered that residue 135 is critical in both lethality and mitogenicity, while mutations in residues 132 and 136 caused the protein to lose its ability to cause TSS, however there were still signs of superantigenicity. [13] If the lysine at residue 132 in TSST-O is changed to a glutamate, the mutant regains little superantigenicity, but becomes lethal, meaning that the ability to cause TSS results from the glutamate at residue 132. [12] [13] The loss of activity from these mutations is not due to changes in the protein's conformation, but instead these residues appear to be critical in the interactions with T-cell receptors. [13]

Isolation

Samples of TSST-1 can be purified from bacterial cultures to use in in vitro testing environments, however this is not ideal due to the large number of factors that contribute to pathenogenesis in an in vivo environment. [8] Additionally, culturing bacteria in vitro provides an environment which is rich in nutrients, in contrast to the reality of an in vivo environment, in which nutrients tend to be more scarce. [8] TSST-1 can be purified by preparative isoelectric focusing for use in vitro or for animal models using a mini-osmotic pump. [14]

Mechanism

A superantigen such as TSST-1 stimulates human T cells that express VB 2, which may represent 5-30% of all host T cells. PTSAgs induce the VB-specific expansion of both CD4 and CD8- subsets of T-lymphocytes. TSST-1 forms homodimers in most of its known crystal forms. [1] The SAGs show remarkably conserved architecture and are divided into the N- and C- terminal domains. Mutational analysis has mapped the putative TCR binding region of TSST-1 to a site located on the back-side groove. If the TCR occupies this site, the amino terminal alpha helix forms a large wedge between the TCR and MHC class II molecules. The wedge would physically separate the TCR from the MHC class II molecules. A novel domain may exist in the SAGs that is separate from the TCR and class II MHC-binding domains. The domain consists of residues 150 to 161 in SEB, and similar regions exist in all the other SAGs as well. In this study a synthetic peptide containing this sequence was able to prevent SAG-induced lethality in D-galactosamine-sensitized mice with staphylococcal TSST-1, as well as some other SAGs. [1] [15] Significant differences exist in the sequences of MHC Class II alleles and TCR Vbeta elements expressed by different species, and these differences have important effects on the interaction of PTSAgs and with MCH class II and TCR molecules.

Binding site

TSST-1 binds primarily to the alpha-chain of class II MHC exclusively through a low-affinity (or generic) binding site on the SAG N-terminal domain. This is opposed to other super antigens (SAGs) such as DEA and SEE, that bind to class II MHC through the low-affinity site, and to the beta-chain through a high-affinity site. This high-affinity site is a zinc-dependent site on the SAG C-terminal domain. When this site is bound, it extends over part of the binding groove, makes contacts with the bound peptide, and then binds regions of both the alpha and beta chains. [15] MHC-binding by TSST-1 is partially peptide-dependent. Mutagenesis studies with SEA have indicated that both binding sites are required for optimal T-cell activation. These studies containing TSST-1 indicate that the TCR binding domain lies at the top of the back side of this toxin, though the complete interaction remains to be determined. There have also been indications that the TCR binding site of TSST-1 is mapped to the major groove of the central alpha helix or the short amino terminal alpha helix. Residues in the beta claw motif of TSST-1 are known to interact primarily with the invariant region of the Alpha chain of this MHC class II molecule. [1] Residues forming minor contacts with TSST-1 were also identified in the HLA-DR1 β-chain, as well as the antigenic peptide, located in the interchain groove. The arrangement of TSST-1 with respect to the MHC class II molecule imposes steric restriction on the three component complex composed of TSST-1, MHC class II, and the TCR. [1]

Mutational analysis

Initial studies of mutants revealed that residues on the back side of the central alpha helix were required for super antigenic activity. Changing the histidine at position 135 to alanine caused TSST-1 to be neither lethal or superantigenic. Changes in residues that were in close proximity to H135A, also had the effect of diminishing the lethality and superantigenic quality of these mutants. Although most of these mutants did not result in loss of antigenicity of TSST-1. Tests done using mutagenic TSST-1 toxins indicated that the lethal and superantigenic properties are separable. When Lys-132 in TSST-O was changed to a Glu, the resulting mutant became completely lethal but non superantigenic. The same results, lethal but not superantigenic, were found for TSST-1 Gly16Val. Residues Gly16, Glu132, and Gln 136, located on the back of the back-side groove of the putative TCR binding region of TSST-1, it has been proposed that they are also a part of a second functionally lethal site in the TSST-1. [1]

Notes

  1. ↑ When active during bacterial colonisation, this gene locus is also called exp agr, referring to the exponential phase (or log phase) of bacterial growth, before expression of other genes down-regulates agr, and growth enters its stationary phase. [10] [11]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

Staphylococcus aureus is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

<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.

Pathogenicity islands (PAIs), as termed in 1990, are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. Pathogenicity islands are found in both animal and plant pathogens. Additionally, PAIs are found in both gram-positive and gram-negative bacteria. They are transferred through horizontal gene transfer events such as transfer by a plasmid, phage, or conjugative transposon. Therefore, PAIs contribute to microorganisms' ability to evolve.

<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">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

<span class="mw-page-title-main">Dendrotoxin</span> Chemical compound

Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes (Dendroaspis) that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctions. Because of their high potency and selectivity for potassium channels, dendrotoxins have proven to be extremely useful as pharmacological tools for studying the structure and function of these ion channel proteins.

Amatoxin is the collective name of a subgroup of at least nine related toxic compounds found in three genera of poisonous mushrooms and one species of the genus Conocybe. Amatoxins are lethal in even small doses, as little as half a mushroom, including the immature "egg" form which appears quite different from the fully-grown mushroom.

'Staphylococcus aureus delta toxin is a toxin produced by Staphylococcus aureus. It has a wide spectrum of cytolytic activity.

<span class="mw-page-title-main">Streptococcal pyrogenic exotoxin</span>

Streptococcal pyrogenic exotoxins also known as erythrogenic toxins, are exotoxins secreted by strains of the bacterial species Streptococcus pyogenes. SpeA and speC are superantigens, which induce inflammation by nonspecifically activating T cells and stimulating the production of inflammatory cytokines. SpeB, the most abundant streptococcal extracellular protein, is a cysteine protease. Pyrogenic exotoxins are implicated as the causative agent of scarlet fever and streptococcal toxic shock syndrome. There is no consensus on the exact number of pyrogenic exotoxins. Serotypes A-C 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. Erythrogenic toxins are known to damage the plasma membranes of blood capillaries under the skin and produce a red skin rash. 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. Bacteriophage T12 infection of S. pyogenes enables the production of speA, and increases virulence.

<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.

SaPIs are a family of ~15 kb mobile genetic elements resident in the genomes of the vast majority of S. aureus strains. Much like bacteriophages, SaPIs can be transferred to uninfected cells and integrate into the host chromosome. Unlike the bacterial viruses, however, integrated SaPIs are mobilized by host infection with "helper" bacteriophages. SaPIs are used by the host bacteria to co-opt the phage reproduction cycle for their own genetic transduction and also inhibit phage reproduction in the process.

<span class="mw-page-title-main">Alpha-neurotoxin</span> Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

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.

Ergtoxin is a toxin from the venom of the Mexican scorpion Centruroides noxius. This toxin targets hERG potassium channels.

<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

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.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Dinges MM, Orwin PM, Schlievert PM (January 2000). "Exotoxins of Staphylococcus aureus". Clinical Microbiology Reviews. 13 (1): 16–34, table of contents. doi:10.1128/CMR.13.1.16. PMC   88931 . PMID   10627489.
  2. ↑ Todar K (2012). "Bacterial Protein Toxins". Todar's Online Textbook of Bacteriology. Madison, Wisconsin.
  3. ↑ Edwin C, Parsonnet J, Kass EH (December 1988). "Structure-activity relationship of toxic-shock-syndrome toxin-1: derivation and characterization of immunologically and biologically active fragments". The Journal of Infectious Diseases. 158 (6): 1287–95. doi:10.1093/infdis/158.6.1287. PMID   3198939.
  4. 1 2 Bushra JS (27 April 2020). Davis CP (ed.). "Toxic Shock Syndrome Causes". eMedicineHealth.com. WebMD, Inc. Retrieved 28 March 2012.
  5. 1 2 3 4 McCormick JK, Tripp TJ, Llera AS, Sundberg EJ, Dinges MM, Mariuzza RA, Schlievert PM (August 2003). "Functional analysis of the TCR binding domain of toxic shock syndrome toxin-1 predicts further diversity in MHC class II/superantigen/TCR ternary complexes". Journal of Immunology. Baltimore, Md. 171 (3): 1385–92. doi: 10.4049/jimmunol.171.3.1385 . PMID   12874229. S2CID   6685050.
  6. 1 2 3 4 Blomster-Hautamaa DA, Kreiswirth BN, Kornblum JS, Novick RP, Schlievert PM (November 1986). "The nucleotide and partial amino acid sequence of toxic shock syndrome toxin-1". The Journal of Biological Chemistry. 261 (33): 15783–6. doi: 10.1016/S0021-9258(18)66787-0 . PMID   3782090.
  7. 1 2 Yarwood JM, McCormick JK, Schlievert PM (February 2001). "Identification of a novel two-component regulatory system that acts in global regulation of virulence factors of Staphylococcus aureus". Journal of Bacteriology. 183 (4): 1113–23. doi:10.1128/JB.183.4.1113-1123.2001. PMC   94983 . PMID   11157922.
  8. 1 2 3 Cunningham R, Cockayne A, Humphreys H (March 1996). "Clinical and molecular aspects of the pathogenesis of Staphylococcus aureus bone and joint infections". Journal of Medical Microbiology. 44 (3): 157–64. doi: 10.1099/00222615-44-3-157 . PMID   8636931.
  9. 1 2 Iandolo JJ (1989). "Genetic analysis of extracellular toxins of Staphylococcus aureus". Annual Review of Microbiology. 43: 375–402. doi:10.1146/annurev.mi.43.100189.002111. PMID   2679358.
  10. ↑ Dufour P, Jarraud S, Vandenesch F, Greenland T, Novick RP, Bes M, et al. (February 2002). "High genetic variability of the agr locus in Staphylococcus species". Journal of Bacteriology. 184 (4): 1180–1186. doi: 10.1128/jb.184.4.1180-1186.2002 . PMC   134794 . PMID   11807079.
  11. ↑ Novick RP (June 2003). "Autoinduction and signal transduction in the regulation of staphylococcal virulence". Molecular Microbiology. 48 (6): 1429–1449. doi: 10.1046/j.1365-2958.2003.03526.x . PMID   12791129. S2CID   6847208.
  12. 1 2 3 4 Murray DL, Prasad GS, Earhart CA, Leonard BA, Kreiswirth BN, Novick RP, Ohlendorf DH, Schlievert PM (January 1994). "Immunobiologic and biochemical properties of mutants of toxic shock syndrome toxin-1". Journal of Immunology. 152 (1): 87–95. doi: 10.4049/jimmunol.152.1.87 . PMID   8254210. S2CID   21088270.
  13. 1 2 3 Murray DL, Earhart CA, Mitchell DT, Ohlendorf DH, Novick RP, Schlievert PM (January 1996). "Localization of biologically important regions on toxic shock syndrome toxin 1". Infection and Immunity. 64 (1): 371–4. doi:10.1128/iai.64.1.371-374.1996. PMC   173772 . PMID   8557369.
  14. ↑ De Boer ML, Kum WW, Chow AW (November 1999). "Interaction of staphylococcal toxic shock syndrome toxin-1 and enterotoxin A on T cell proliferation and TNFα secretion in human blood mononuclear cells". The Canadian Journal of Infectious Diseases. 10 (6): 403–8. doi: 10.1155/1999/234876 . PMC   3250724 . PMID   22346398.
  15. 1 2 McCormick JK, Yarwood JM, Schlievert PM (2001). "Toxic shock syndrome and bacterial superantigens: an update". Annual Review of Microbiology. 55: 77–104. doi:10.1146/annurev.micro.55.1.77. PMID   11544350.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.