Phenol-soluble modulin

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.[1] 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.[2] 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.

Although PSMs are present in every Staphylococcal species, there is still diversity. Staphylococcus aureus encodes eight different PSMs, PSMα 1-4, PSMβ 1-2, PSMγ (Also known as δ-toxin in S. aureus), and PSM-mec.[3] While Staphylococcus epidermidis encodes one PSMα, PSMβ 1-2, PSMγ, and PSM-mec.[3] In addition S. epidermidis encodes two unique PSMs, PSMδ and PSMε.[3]

PSM-mec is one of the most widely encoded PSM among Staphylococcal species. Which may be in part due to PSM-mec being encoded on the mecI mobile genetic element.[3]

Structure and location

As the PSM classes are closely related there are many conserved aspects. However each PSM class plays a different role, as such there are some distinctive features for each. Generally PSMs are encoded on the core genome of staphylococcal species however some, such as PSM-mec, are encoded on mobile genetic elements. PSMs are generally separated into one of two classes α-type PSMs and β-type PSMs, which are based upon characteristics of the two most well studied PSMs PSMα and PSMβ.

PSMα

PSMα forms an amphipathic α-helix structure that composes the entire length of the peptide.[2] These peptides are relatively short, being composed of only 20-25 amino acids.[2] With regards to charge, α-type PSMs generally have a neutral charge, but may also be slightly positive.[2]

PSMβ

PSMβ Are similar to PSMα in that they contain an amphipathic α-helix.[2] However, the helix does not compose the entirety of the peptide, instead covering only the C-terminus of the peptide.[2] PSMβ are generally larger that PSMα, being composed of 43-45 amino acids.[2] Unlike α-type PSMs, β-type PSMs usually possess a negative charge.[2]

PSMγ

PSMγ (also known as δ-Toxin) shares some homology with PSMα-3 encoded by S. aureus.[3]

PSMδ

PSMδ is encoded downstream of the PSMα gene in S. epidermidis.[3] In addition PSMδ shares some homology with PSMγ.[3]

PSMε

Little work has been done to determine the structure of PSMε. However it is believed to play a role in both biofilm formation as well as inflammation.[3]

PSM-mec

PSM-mec is encoded on the Staphylococcal Chromosomal Cassette methicillin resistance island (SCCmec) which encodes genes associated with methicillin resistance in different Staphylococcal species.[3] Little work has been done to determine the exact structure of PSM-mec.

Regulation

PSM regulation in S. aureus is primarily controlled by the agr system.[2] The exact mechanism of regulation differs from other agr controlled toxins, which are controlled by the agr effector molecule RNAIII. PSMs, however, are controlled by direct binding of AgrA to the promoter region.[2] PSM-mec RNA has been implicated in the regulation of the agr system and as a result can influence the expression of other PSMs.[2] In addition to the agr system, SarA as well as LuxS have both been implicated in PSM control, with mutations in either system showing decreased levels of PSM production.[3] In addition the MgrA system has been shown to alter biofilm formation, via suppression of PSMs.[4] The environment S. aureus is exposed to has been demonstrated to play a role in PSM expression. In intracellular environments it has been shown that PSM production is increased.[2]

In addition to being the subject of regulation, PSMs have been shown to regulate other toxins such as S. aureus alpha toxin.[5]

Functions

Inflammation

PSMs were first described as a pro-inflammatory molecule.[2] This role has been repeatedly demonstrated to be true. PSMs are able to induce the production of a variety of cytokines as well as induce neutrophils to migrate to sites of infection.[3] PSMε in S. epidermidis is known to influence the production of IL-8.[3] PSMα in S. aureus has been shown to influence IL-17 levels during infection.[6]

In addition to their pro-inflammatory properties, PSMs have been shown to be directly sensed by circulating leucocytes through the formyl peptide receptor FPR2, thus driving a rapid, pathogen-specific attraction of neutrophiles to the site of infection, via an EGR1-dependent signalling pathway.[7]

Infection

In addition to their role in attracting neutrophils to sites of infection, PSMs can also influence the function of neutrophils. It has been demonstrated that secreted PSMs are able to induce Neutrophil Extracellular Trap release.[8] The PSMs also have been shown to decrease the number of persister cells within a population of S. aureus.[9]

MRSA production of PSMs is thought to be a possible cause of severe infections.[10] PSM production is higher in community-acquired MRSA (CA-MRSA) than in healthcare-associated MRSA (HA-MRSA),[11] and consequently CA-MRSA associated osteomyelitis[11] is more severe than HA-MRSA associated osteomyelitis.

Cell lysis

Many PSMs have cytolytic activity and play a major role in the nonspecific lysing of host cells, including Polymorphonuclear Neutrophils (PMNs).[2] Lysis is carried out by integration of PSMs into membranes, in a nonspecific fashion, which results in disruption of the membrane.[2] Different PSMs are able to lyse cells with different affinities. PSMα, in S. aureus, and PSMδ, in S. epidermidis, are the most potent cytolysins.[2] WHile highly cytolytic PSMs, such as PSMα and PSMδ, are generally α-type PSMs the β-type PSMs tend to be less cytolytic.[2]

Colony spreading

S. aureus is a non-motile bacteria, and must rely on alternative forms of spreading. Phenol-Soluble Modulins have been implicated in assisting with colony spreading.[12] PSMα 1-4 have been shown to help S. aureus colonies spread on agar plates.[12] However, δ-Toxin, which is another α-class PSM, does not play a role in colony spreading.[12]

Biofilm

While the α-type PSMs are regarded as major cytolysins, the β-type PSMs are thought to play a role in biofilm formation.[2] S. epidermidis, which is a known opportunistic pathogen, has a high level of β-type PSM expression.[2] In addition in vitro measurement of PSMβ expression in S. epidermidis has shown to be increased in biofilm as opposed to planktonic growth, further suggesting a link between PSMβ and biofilm formation.[2] Altering the structure of PSMβ has been demonstrated to disrupt their ability to influence biofilm formation.[3]

References
  1. Berube, Bryan J.; Sampedro, Georgia R.; Otto, Michael; Bubeck Wardenburg, Juliane (2014-08-01). "The psmα locus regulates production of Staphylococcus aureus alpha-toxin during infection". Infection and Immunity. 82 (8): 3350–3358. doi:10.1128/IAI.00089-14. ISSN 1098-5522. PMC 4136214. PMID 24866799.
  2. 1. Cheung GYC, Joo HS, Chatterjee SS, Otto M. Phenol-soluble modulins - critical determinants of staphylococcal virulence. FEMS Microbiology Reviews. Blackwell Publishing Ltd; 2014. pp. 698–719. doi:10.1111/1574-6976.12057
  3. Li S, Huang H, Rao X, Chen W, Wang Z, Hu X. Phenol-soluble modulins: novel virulence-associated peptides of staphylococci REVIEW. Futur Microbiol. 2014;9: 203–216. doi:10.2217/FMB.13.153
  4. Jiang Q, Jin Z, Sun B. MgrA negatively regulates biofilm formation and detachment by repressing the expression of psm operons in Staphylococcus aureus. Appl Environ Microbiol. 2018;84: 1–17. doi:10.1128/AEM.001008-18
  5. Berube BJ, Sampedro GR, Otto M, Wardenburg JB. The psmα locus regulates production of Staphylococcus aureus alpha-toxin during infection. Infect Immun. 2014;82: 3350–3358. doi:10.1128/IAI.00089-14
  6. Yang G, Sau C, Lai W, Cichon J, Li W. Staphylococcus aureus virulent PSMα peptides induce keratinocyte alarmin release to orchestrate IL-17-dependent skin inflammation. 2015;344: 1173–1178. doi:10.1126/science.1249098.Sleep
  7. Nguyen TH, Cheung, GYC, Rigby KM, et al. Rapid pathogen-specific recruitment of immune effector cells in the skin by secreted toxins. Nat Microbiol. 2022 Jan;7(1):62-72. doi:10.1038/s41564-021-01012-9
  8. Björnsdottir H, Rudin AD, Klose FP, Elmwall J, Welin A, Stylianou M, et al. Phenol-soluble modulin a peptide toxins from aggressive Staphylococcus aureus induce rapid formation of neutrophil extracellular traps through a reactive oxygen species-independent pathway. Front Immunol. 2017;8. doi:10.3389/fimmu.2017.00257
  9. Bojer MS, Lindemose S, Vestergaard M, Ingmer H. Quorum sensing-regulated phenol-soluble modulins limit persister cell populations in Staphylococcus aureus. Front. Microbiol. 2018;9. doi:10.3389/fmicb.2018.00255
  10. Graves, S. F.; Kobayashi, S. D.; Deleo, F. R. (2010). "Community-associated methicillin-resistant Staphylococcus aureus immune evasion and virulence". Journal of Molecular Medicine. 88 (2): 109–114. doi:10.1007/s00109-009-0573-x. PMC 2852573. PMID 20049412.
  11. Rasigade, Jean-Philippe; Trouillet-Assant, Sophie; Ferry, Tristan; Diep, Binh An; Sapin, Anaïs; Lhoste, Yannick; Ranfaing, Jérémy; Badiou, Cédric; Benito, Yvonne (2013-01-01). "PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts". PLOS ONE. 8 (5): e63176. doi:10.1371/journal.pone.0063176. ISSN 1932-6203. PMC 3653922. PMID 23690994.
  12. Kizaki H, Omae Y, Tabuchi F, Saito Y, Sekimizu K, Kaito C. Cell-surface phenol soluble modulins regulate staphylococcus aureus colony spreading. PLoS One. 2016;11: 1–26. doi:10.1371/journal.pone.0164523
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