Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Seilie, E. Sachiko; Wardenburg, Juliane Bubeck

doi:10.1016/j.semcdb.2017.04.003

Cited by 172 publications

(143 citation statements)

References 209 publications

(337 reference statements)

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“…Recently, the GBS hemolysin and pigment were shown to be one and the same (Whidbey et al, 2013), initiating a shift in understanding this virulence factor. The GBS hemolytic pigment, also known as Granadaene (Rosa-Fraile et al, 2006), is a cell surface-associated (Platt, 1995) ornithine rhamnolipid consisting of a 12-alkene chain and is unrelated to other commonly studied Gram-positive pore-forming toxins, such as lysteriolysin O (Hamon et al, 2012) or alpha toxin (Seilie and Bubeck Wardenburg, 2017), which are proteinaceous in nature. Many gaps remain in our understanding of Granadaene, including the specifics of its biosynthesis in bacterial cells and reasons why GBS may have evolved to produce this potent toxin.…”

Section: Introductionmentioning

confidence: 99%

The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene

et al. 2020

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Group B Streptococcus (GBS) is a β-hemolytic, Gram-positive bacterium that commonly colonizes the female lower genital tract and is associated with fetal injury, preterm birth, spontaneous abortion, and neonatal infections. A major factor promoting GBS virulence is the β-hemolysin/cytolysin, which is cytotoxic to several host cells. We recently showed that the ornithine rhamnolipid pigment, Granadaene, produced by the gene products of the cyl operon, is hemolytic. Here, we demonstrate that heterologous expression of the GBS cyl operon conferred hemolysis, pigmentation, and cytoxicity to Lactococcus lactis, a model non-hemolytic Gram-positive bacterium. Similarly, pigment purified from L. lactis is hemolytic, cytolytic, and identical in structure to Granadaene extracted from GBS, indicating the cyl operon is sufficient for Granadaene production in a heterologous host. Using a systematic survey of phyletic patterns and contextual associations of the cyl genes, we identify homologs of the cyl operon in physiologically diverse Gram-positive bacteria and propose undescribed functions of cyl gene products. Together, these findings bring greater understanding to the biosynthesis and evolutionary foundations of a key GBS virulence factor and suggest that such potentially toxic lipids may be encoded by other bacteria.

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Section: Introductionmentioning

confidence: 99%

The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene

et al. 2020

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“…S taphylococcus aureus is a ubiquitous nosocomial organism with a diverse arsenal of virulence factors enabling it to establish infection in any mammalian tissue upon invasion (1)(2)(3)(4). Consequently, S. aureus is a leading cause of infective endocarditis, skin and soft tissue infections, and medical device-associated infections, among other diseases (5,6).…”

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confidence: 99%

PhoPR Contributes to Staphylococcus aureus Growth during Phosphate Starvation and Pathogenesis in an Environment-Specific Manner

2018

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Microbial pathogens must obtain all essential nutrients, including phosphate, from the host. To optimize phosphate acquisition in diverse and dynamic environments, such as mammalian tissues, many bacteria use the PhoPR two-component system. Despite the necessity of this system for virulence in several species, PhoPR has not been studied in the major human pathogen To illuminate its role in staphylococcal physiology, we initially assessed whether PhoPR controls the expression of the three inorganic phosphate (P) importers (PstSCAB, NptA, and PitA) in This analysis revealed that PhoPR is required for the expression of and and can modulate expression. Consistent with a role in phosphate homeostasis, PhoPR-mediated regulation of the transporters is influenced by phosphate availability. Further investigations revealed that PhoPR is necessary for growth under P-limiting conditions, and in some environments, its primary role is to induce the expression of or Interestingly, in other environments, PhoPR is necessary for growth independent of P transporter expression, indicating that additional PhoPR-regulated factors promote adaptation to low-P conditions. Together, these data suggest that PhoPR differentially contributes to growth in an environment-specific manner. In a systemic infection model, a mutant of lacking PhoPR is highly attenuated. Further investigation revealed that PhoPR-regulated factors, in addition to P transporters, are critical for staphylococcal pathogenesis. Cumulatively, these findings point to an important role for PhoPR in orchestrating P acquisition as well as transporter-independent mechanisms that contribute to virulence.

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“…Pore-forming proteins are widely used as toxins to target either prokaryotic or eukaryotic cells 33, 34 . To determine whether TspA forms pores we used single-cell microscopy that combines the voltage-sensitive dye DiSC 3 (5) with the membrane-impermeable nucleic acid stain Sytox Green 35 .…”

Section: Resultsmentioning

confidence: 99%

A membrane-depolarizing toxin substrate of theStaphylococcus aureusType VII secretion system mediates intra-species competition

Ulhuq

Duggan

Guo

et al. 2018

Preprint

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21 22 † for correspondence tracy.palmer@newcastle.ac.uk 23 24 25 26 42 45 proteins that are essential for virulence and immune evasion 1 . The Ess T7SS of 46Staphylococcus aureus is also required for pathogenesis in murine models of infection 2, 3, 4 , 47 and a longitudinal study of persistent S. aureus infection in the airways of a cystic fibrosis 48 patient showed that the ess T7SS genes were highly upregulated during a 13 year timespan 5 . 49It is becoming increasingly apparent, however, that in addition to having anti-eukaryotic 50 activity, the T7SS of firmicutes mediates interbacterial competition 6, 7, 8 . Some strains of S. 51aureus secrete a DNA endonuclease toxin, EsaD 6, 9 , that when overproduced leads to growth 52 inhibition of a sensitive S. aureus strain 6 . Moreover, Streptococcus intermedius exports at 53 least three LXG domain-containing toxins, TelA, TelB and TelC that mediate contact-54 dependent growth inhibition against a range of Gram positive species 7 . 55A large integral membrane ATPase of the FtsK/SpoIIIE family, termed EssC in firmicutes, is a 56 conserved component of all T7SSs and probably energizes protein secretion as well as 57 forming part of the translocation channel 10, 11, 12, 13 . Three further membrane proteins function 58 alongside the ATPase to mediate T7 protein secretion 2, 3, 13, 14, 15 . EsxA, a small secreted 59 protein of the WXG100 family, is a further conserved T7 component that is dependent on the 60 T7SS for its translocation across the membrane 2, 16 . In S. aureus the T7 structural components 61 are encoded at the ess locus. In commonly-studied S. aureus strains including Newman, 62RN6390 and USA300, the T7 substrates EsxB, EsxC, EsxD and EsaD are encoded 63 immediately downstream of essC ( Fig 1A) and are co-regulated with the genes coding for 64 machinery components 2, 3, 6, 9, 17, 18 . With the exception of EsaD the biological activities of these 65 substrates are unknown, although mutational studies have suggested that EsxB and EsxC 66 contribute to persistent infection in a murine abscess model 2, 17 . 67Despite the ess locus forming part of the core S. aureus genome, these four substrate proteins 68 are not conserved across S. aureus isolates, being found in only approximately 50% of a similar decrease in kidney abscess formation as that seen for T7 mutants in Newman and 71 USA300 2, 4, 20 , despite the fact that recognizable homologues of EsxB/EsxC/EsxD/EsaD are 72 not encoded by this strain 19 . This strongly suggests that there are further S. aureus T7 73 substrates that are yet to be identified. Here we have taken an unbiased approach to identify 74 T7 substrates using quantitative proteomic analysis of culture supernatants from S. aureus 75 RN6390 wild type and essC strains. We identify a new substrate, TspA that is encoded 76 distantly from the ess gene cluster and is found in all sequenced S. aureus strains. Further 77 analysis indicates that TspA has a toxic C-terminal domain that depolarizes membranes. 78Using a zebrafish hindbrain ventricle ...

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Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

Cited by 172 publications

References 209 publications

The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene

The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene

PhoPR Contributes to Staphylococcus aureus Growth during Phosphate Starvation and Pathogenesis in an Environment-Specific Manner

A membrane-depolarizing toxin substrate of theStaphylococcus aureusType VII secretion system mediates intra-species competition

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