Lecture 7: S. aureus determinants

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  • Created on: 04-01-19 11:25
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  • S. aureus determinants
    • Properties
      • Gram +, facultative anaerobe, opportunistic pathogen causing conjunctivitis, skin infections, pneumonia, toxic shock syndrome
        • Tight regulation of VF - exotoxins, modulins, leukicidins, exoenzymes, enterotoxins = growth and survival adv, adaptability to different niches, adherence to host and evasion of IS
        • Attachment to the host cell regulated by = fibronectin binding prot, clumping factor, elastin bp, adhesion prot, ECM prot and LSD proteins. 
        • Evasion occurs via Protein A - inhibits phagocytosis, Staphylokinase which cleaves complement, polysacc capsules-  inhibit access of neutrophils, chemotaxis inhibitory proteins, coagulase which inhibits WBC penetration and catalase.
        • There are also various exoenzymes and exotoxins which include: hyaluronidase, lipases, nucleases, proteases, alpha, beta and delta toxin, modulins, leukicidins, exfoliation toxins associated with toxic shock syndrome.
    • Quorum sensing
      •  In the activated quorum sensing system, as the cell density increases, the agr system promotes the expression of secreted VF and downregs production of cells surface proteins  from late exponential to stationary phase.
      • Two regulators: agr and SarA
        • Agr is the accessory gene regular and sarA is the staphylococcal accessory regulator involved in transcriptional regulation.
        • Pathogenesis stages
          • Early Pathogenesis -  In early pathogenesis, staphylococci will initially be present in small numbers and just express VF to evade the IS. For example, protein A binds to the Fc region of IgG and clumping factors help to create a wall for the infection site. Typically, protein adhesins are produced during the exponential phase of growth.
          • The second stage of infection occurs post-exponentially and characterised by enhanced toxin and enzyme production leading to tissue destruction and bacterial spread. The regulatory events controlling the transition from exponential to post are mediated in part by agr which when activated, represses surface proteins and promotes secretion of the second stage toxins.
          • SarA and agr: SarA activates agr expression and binds directly to P2 and P3 promoters. Expression contributes to staphylococcapathogenesis for example, abscesses and arthritis as well as invasion and apoptosis of endothelial cells. 
          • SarA is a DNA binding protein and binds to promoters to alter virulence gene expression. Another member of the Sar family, SarR has been shown to bind to the SarA promoter to repress SarA expression. Inactivation of SarR also affects agr regulation.
          • RNA II and III are generated by the agr locus and originate from the P2 (RNAII) and P3 (RNAIII) promoter. The P2 operon encodes for 4 proteins: Agr A, B, C and D. AgrA and C form a two-component regulation system in which AgrC (histidine kinase) binds the extracellular AIP (cyclic autoinducing peptide) which results in increased P2 and P3 transcription in its log phase when the concentration of the signal is high. AgrB is a transmembrane protein involved in the processing of AgrD into an octapeptide, secretion of the AIP and modification of the AIP so all four proteins have interlinking roles.
          • RNAIII also encodes for delta-hemolysin and increases transcription of VF’s such as the TSS-1 and hemolysins. Agr via SarS which is inhibited by RNAIII can activate Spa (Protein A). Spa is present is 90% of S. aureus strains and activates complement in vitro. It has been demonstrated than strains with high Spa are more resistant to phagocytosis.
    • Biofilm formation
      • Many staphylococci infections are not caused by the organism but by biofilms. Biofilms are a community of cells attached by an abiotic or biotic surface and encased in a self-produced matrix and exhibit altered growth and gene expression. They are also heavily resistant to antibiotic therapy and clearance by hosts natural defences. 
      • Two stages of formation occur: the first is attachment of the cells to a surface, this is mediated by adhesins and the second includes cell multiplication and formation of a multi-layered community. This stage is associated with extracellular factors including the PIA adhesin.
      • One intriguing idea is that quorum sensing impact the growth and development of biofilm formation and that agr may influence attachment, dispersal and infectious behaviour.
      • To conclude, this essay has discussed the role of Agr and the Sar family in pathogenesis and biofilm formation. Potential drugs could include: agr inhibitors, sarA inhibitors and a vaccine but the limitations with this arise from an inflammation response which could have potential undesirable side effects
      • The studies undertaken have been somewhat limited. In the Pratten et al study, they found little different between WT S. aureus and agr mutant in adherence on uncoated and fibronectin coated glass. In another study, RNAIII expression decrease S. aureus adherence to fibrinogen but increased adherence to fibronectin. Vuong et al found that S. aureus strains with a non-functional agr were much more likely to form biofilms and that the alpha toxin was positive regulated by the agr system so conflicting studies.

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