Staphylococcus aureus delta toxin

Last updated
Delta-hemolysin
Identifiers
Organism Staphylococcus aureus
Symbolhld
Entrez 3919680
PDB 2KAM
RefSeq (Prot) WP_000046022.1
UniProt P0C1V1
Other data
Chromosome genome: 2.09 - 2.09 Mb

'Staphylococcus aureus delta toxin is a toxin produced by Staphylococcus aureus . [1] It has a wide spectrum of cytolytic activity. [2]

Contents

It is among other toxins produced by S. aureus and is part of the phenol-soluble modulin peptide family. [3] Its alpha-helical, amphipathic structure gives it detergent-like properties, allowing it to disrupt and attach to the cytoplasmic membrane of a cell non-specifically, without a receptor, and integrate into the membrane. [4] [5] Delta toxin degrades the membrane on contact and forms short-lived pores, causing cell lysis and subsequent cell death. [5]

Structure

S. aureus delta toxin is encoded for by the hld gene. [6] The hld gene, of which the 3’ end encodes for delta toxin, is involved in the accessory gene regulator (agr) system. This system controls the signaling and creation of cell-associated and secreted virulence factors. Delta toxin is also secreted from S. aureus without a signal peptide, but the toxin itself has been speculated to make an effective signal peptide. The S. aureus delta toxin molecule has been speculated to oligomerize and form cation-selective ion channels in the membrane for use other than cell lysis by the toxin. The channel is proposed to be formed by six delta toxin molecules in a hexagonal arrangement. [7]

Function

Staphylococcus aureus delta toxin is a phenol-soluble modulin peptide. Because of this, the cytotoxins that are produced upon a S. aureus infection, including delta toxin, are proinflammatory molecules. Delta toxin is also a chemoattractant for leukocytes, leading to a surge of cytokines such as interleukin-8 from neutrophils at an infection site. [5] Delta toxin molecules activate a G-protein-coupled receptor expressed in leukocytes called formyl-peptide receptor 2 (FPR2), which binds metabolites to inhibit and lower inflammation. Thus, delta toxin molecules trigger inflammation that needs to be modulated by FPR2. [5]

Delta toxin also has moderate cytolytic abilities to lyse red and white blood cells through the use of short-lived pores in the cytoplasmic membrane. The toxin then uses host tissue as nutrients required for further S. aureus bacteria growth. Delta toxin specifically causes mast cell degranulation, contributing to allergic reactions of the skin like atopic dermatitis. This reaction is only caused by delta toxin, rather than the other toxins produced by S. aureus, proving that PSM peptides have evolved to fulfill different roles in pathogenesis. [5]

PSMs, like S. aureus delta toxin, can prevent the activation and proliferations of CD4+ T cells, depending on interleukin-10 and TFG-beta activations. This would result in a down regulation of the adaptive immune response, potentially increasing pathogenic tolerance. This is a hypothesis as to why S. aureus is so virulent; S. aureus bacteria are able to modulate the organism’s immune system to evade it. [8]

Delta toxin is quite heat-stable, unlike S. aureus alpha and beta toxins. [9] However, the addition of lecithin specifically prevents delta toxin from lysing cells. Delta toxin activity can also both enhanced and prevented with saturated, straight-chain fatty acids of varying lengths. Phospholipids 13 to 19 carbons in length enhanced the lytic activity of delta toxin, whereas those that were 21 to 23 carbons long were inhibitory. The length of the fatty acid chain could be related to the binding of the toxin to the membrane to be effective, as those phospholipids with longer tails prevent the toxin from getting close enough to the membrane. [10]

Related Research Articles

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

Staphylococcus aureus is a Gram-positive, round-shaped bacterium, a member of the Firmicutes, 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. The emergence of antibiotic-resistant strains of S. aureus 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.

Exotoxin

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.

Enterotoxin

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines.

Virulence factors are molecules produced by bacteria, viruses, fungi, and protozoa that add to their effectiveness and enable them to achieve the following:

Panton–Valentine leukocidin

Panton–Valentine leukocidin (PVL) is a cytotoxin—one of the β-pore-forming toxins. The presence of PVL is associated with increased virulence of certain strains (isolates) of Staphylococcus aureus. It is present in the majority of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates studied and is the cause of necrotic lesions involving the skin or mucosa, including necrotic hemorrhagic pneumonia. PVL creates pores in the membranes of infected cells. PVL is produced from the genetic material of a bacteriophage that infects Staphylococcus aureus, making it more virulent.

Cytolysin refers to the substance secreted by microorganisms, plants or animals that is specifically toxic to individual cells, in many cases causing their dissolution through lysis. Cytolysins that have a specific action for certain cells are named accordingly. For instance, the cytolysins responsible for the destruction of red blood cells, thereby liberating hemoglobins, are named hemolysins, and so on. Cytolysins may be involved in immunity as well as in venoms.

Pore-forming toxin

Pore-forming proteins are usually produced by bacteria, and include a number of protein exotoxins but may also be produced by other organisms such as earthworms, who produce lysenin. They are frequently cytotoxic, as they create unregulated pores in the membrane of targeted cells.

Hemolysin Molecule destroying the membrane of red blood cells

Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acquisition, many hemolysins produced by pathogens do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.

RNAIII is a stable 514 nt regulatory RNA transcribed by the P3 promoter of the Staphylococcus aureus quorum-sensing agr system ). It is the major effector of the agr regulon, which controls the expression of many S. aureus genes encoding exoproteins and cell wall associated proteins plus others encoding regulatory proteins The RNAIII transcript also encodes the 26 amino acid δ-haemolysin peptide (Hld). RNAIII contains many stem loops, most of which match the Shine-Dalgarno sequence involved in translation initiation of the regulated genes. Some of these interactions are inhibitory, others stimulatory; among the former is the regulatory protein Rot. In vitro, RNAIII is expressed post exponentially, inhibiting translation of the surface proteins, notably protein A, while stimulating that of the exoproteins, many of which are tissue-degrading enzymes or cytolysins. Among the latter is the important virulence factor, α-hemolysin (Hla), whose translation RNAIII activates by preventing the formation of an inhibitory foldback loop in the hla mRNA leader.

Listeriolysin O (LLO) is a hemolysin produced by the bacterium Listeria monocytogenes, the pathogen responsible for causing listeriosis. The toxin may be considered a virulence factor, since it is crucial for the virulence of L. monocytogenes.

<i>Staphylococcus aureus</i> alpha toxin

Alpha-toxin, also known as alpha-hemolysin (Hla), is the major cytotoxic agent released by bacterium Staphylococcus aureus and the first identified member of the pore forming beta-barrel toxin family. This toxin consists mostly of beta-sheets (68%) with only about 10% alpha-helices. The hly gene on the S. aureus chromosome encodes the 293 residue protein monomer, which forms heptameric units on the cellular membrane to form a complete beta-barrel pore. This structure allows the toxin to perform its major function, development of pores in the cellular membrane, eventually causing cell death.

Toxic shock syndrome toxin (TSST) 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.

Phenol-soluble modulins (PSMs) are a family of small proteins, that carry out a variety of functions, including acting as toxins, assisting in biofilm formation, and colony spreading. PSMs are produced by Staphylococcus bacteria including Methicillin-resistant Staphylococcus aureus (MRSA), and Staphylococcus epidermidis. Many PSMs are encoded within the core genome and can play an important virulence factor. PSMs were first discovered in S. epidermidis by Seymour Klebanoff and via hot-phenol extraction and were described as a pro-inflammatory complex of three peptides. Since their initial discovery, numerous roles of PSMs have been identified. However, due in part to the small size of many PSMs, they have largely gone unnoticed until recent years.

Aureolysin

Aureolysin is an extracellular metalloprotease expressed by Staphylococcus aureus. This protease is a major contributor to the bacterium's virulence, or ability to cause disease, by cleaving host factors of the innate immune system as well as regulating S. aureus secreted toxins and cell wall proteins. To catalyze its enzymatic activities, aureolysin requires zinc and calcium which it obtains from the extracellular environment within the host.

Staphylococcus schleiferi is a Gram-positive, cocci-shaped bacterium of the Family Staphylococcaceae. It is facultatively anaerobic, coagulase-variable, and can be readily cultured on blood agar where the bacterium tends to form opaque, non-pigmented colonies and beta (β) hemolysis. There exists two subspecies under the species S. schleiferi: Staphylococcus schleiferi subsp. schleiferi and Staphylococcus schleiferi subsp. coagulans.

Staphylococcus pseudintermedius is a gram positive coccus bacteria of the genus Staphylococcus found worldwide. It is primarily a pathogen for domestic animals, but has been known to affect humans as well.S. pseudintermedius is an opportunistic pathogen that secretes immune modulating virulence factors, has many adhesion factors, and the potential to create biofilms, all of which help to determine the pathogenicity of the bacterium. Diagnoses of Staphylococcus pseudintermedius have traditionally been made using cytology, plating, and biochemical tests. More recently, molecular technologies like MALDI-TOF, DNA hybridization and PCR have become preferred over biochemical tests for their more rapid and accurate identifications. This includes the identification and diagnosis of antibiotic resistant strains.

Teixobactin is a peptide-like secondary metabolite of some species of bacteria, that kills some gram-positive bacteria. It appears to belong to a new class of antibiotics, and harms bacteria by binding to lipid II and lipid III, important precursor molecules for forming the cell wall.

The SprA1/SPrA1as toxin/antitoxin system identified in Staphylococcus aureus, belongs to the Type I system encoding toxin protein: SprA1 and antitoxin RNA: SprA1as. The SprA1as postranscriptionally regulates SprA1 encoding small membrane damaging protein PepA1.

Nutritional immunology

Nutritional immunology is a field of immunology that focuses on studying the influence of nutrition on the immune system and its protective functions. Part of nutritional immunology involves studying the possible effects of diet on the prevention and management on developing autoimmune diseases, chronic diseases, allergy, cancer and infectious diseases. Other related topics of nutritional immunology are: malnutrition, malabsorption and nutritional metabolic disorders including the determination of their immune products.

Accessory gene regulator (agr) is a complex 5 gene locus that is a global regulator of virulence in Staphylococcus aureus. It encodes a two-component transcriptional quorum-sensing (QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP).

References

  1. ↑ Nolte FS, Kapral FA (March 1981). "Immunogenicity of Staphylococcus aureus delta-toxin". Infection and Immunity. 31 (3): 1251–60. PMC   351449 . PMID   7014461.
  2. ↑ Murray PR, Rosenthal KS, Pfaller MA (2009) [1990]. Medical Microbiology (6th ed.). Philadelphia: Mosby. p. 213. ISBN   978-0-323-05470-6.
  3. ↑ Cheung GY, Yeh AJ, Kretschmer D, Duong AC, Tuffuor K, Fu CL, Joo HS, Diep BA, Li M, Nakamura Y, Nunez G, Peschel A, Otto M (December 2015). "Functional characteristics of the Staphylococcus aureus δ-toxin allelic variant G10S". Scientific Reports. 5 (1): 18023. doi:10.1038/srep18023. PMC   4674873 . PMID   26658455.
  4. ↑ Bloes DA, Haasbach E, Hartmayer C, Hertlein T, Klingel K, Kretschmer D, Planz O, Peschel A (December 2017). "Phenol-Soluble Modulin Peptides Contribute to Influenza A Virus-Associated Staphylococcus aureus Pneumonia". Infection and Immunity. 85 (12): e00620–17. doi:10.1128/IAI.00620-17. PMC   5695099 . PMID   28893917.
  5. 1 2 3 4 5 Otto M (February 2014). "Staphylococcus aureus toxins". Current Opinion in Microbiology. 17: 32–7. doi:10.1016/j.mib.2013.11.004. PMC   3942668 . PMID   24581690.
  6. ↑ Universal protein resource accession number P0C1V1 for "Delta-hemolysin" at UniProt.
  7. ↑ 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.
  8. ↑ Schreiner J, Kretschmer D, Klenk J, Otto M, Bühring HJ, Stevanovic S, Wang JM, Beer-Hammer S, Peschel A, Autenrieth SE (April 2013). "Staphylococcus aureus phenol-soluble modulin peptides modulate dendritic cell functions and increase in vitro priming of regulatory T cells". Journal of Immunology. 190 (7): 3417–26. doi:10.4049/jimmunol.1202563. PMC   3608756 . PMID   23460735.
  9. ↑ Thelestam M, Möllby R, Wadström T (December 1973). "Effects of staphylococcal alpha-, beta-, delta-, and gamma-hemolysins on human diploid fibroblasts and HeLa cells: evaluation of a new quantitative as say for measuring cell damage". Infection and Immunity. 8 (6): 938–46. PMC   422954 . PMID   4784889.
  10. ↑ Kapral FA (January 1976). "Effect of fatty acids on Staphylococcus aureus delta-toxin hemolytic activity". Infection and Immunity. 13 (1): 114–9. PMC   420584 . PMID   1248865.


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