Staphylococcus aureus delta toxin

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

Delta-hemolysin
Identifiers
OrganismStaphylococcus aureus
Symbolhld
Entrez3919680
PDB2KAM
RefSeq (Prot)WP_000046022.1
UniProtP0C1V1
Other data
Chromosomegenome: 2.09 - 2.09 Mb

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]

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. 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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