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Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus

Key Points

  • Staphylococcus aureus is a commensal bacterium that can cause both superficial and invasive, potentially life-threatening, infections such as sepsis, endocarditis and pneumonia.

  • S. aureus can express a range of virulence factors, which include surface proteins that are covalently attached to peptidoglycan, known as cell wall-anchored (CWA) proteins.

  • On the basis of structural and functional data, CWA proteins can be grouped into four families: microbial surface component recognizing adhesive matrix molecule (MSCRAMM), near iron transporter (NEAT), three-helical bundle and G5–E repeat proteins.

  • MSCRAMM proteins, which are characterized by at least two adjacent IgG-folded domains in their amino-terminal A region, are the largest family. MSCRAMM proteins can bind to their ligands by a mechanism known as 'dock, lock and latch', or in a variation of this process, known as the 'collagen hug'.

  • S. aureus CWA proteins are important virulence factors that mediate iron acquisition, adhesion, biofilm formation, invasion, inflammation and evasion of innate and adaptive immunity. CWA proteins can be both multifunctional and functionally redundant.

  • CWA protein variation might have a role in defining the virulence of clinical isolates — for example, by increasing adhesion to biomaterial surfaces and indwelling medical devices. Furthermore, recombinant CWA proteins are potential vaccine candidates.

Abstract

Staphylococcus aureus is an important opportunistic pathogen and persistently colonizes about 20% of the human population. Its surface is 'decorated' with proteins that are covalently anchored to the cell wall peptidoglycan. Structural and functional analysis has identified four distinct classes of surface proteins, of which microbial surface component recognizing adhesive matrix molecules (MSCRAMMs) are the largest class. These surface proteins have numerous functions, including adhesion to and invasion of host cells and tissues, evasion of immune responses and biofilm formation. Thus, cell wall-anchored proteins are essential virulence factors for the survival of S. aureus in the commensal state and during invasive infections, and targeting them with vaccines could combat S. aureus infections.

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Figure 1: Functions of CWA proteins of S. aureus.
Figure 2: Classification of CWA proteins on the basis of structural motifs.
Figure 3: Mechanisms of ligand binding by MSCRAMM proteins.
Figure 4: Roles of CWA proteins in biofilm formation.

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References

  1. DeLeo, F. R., Otto, M., Kreiswirth, B. N. & Chambers, H. F. Community-associated meticillin-resistant Staphylococcus aureus. Lancet 375, 1557–1568 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Otto, M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu. Rev. Microbiol. 64, 143–162 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Chambers, H. F. & Deleo, F. R. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature Rev. Microbiol. 7, 629–641 (2009).

    Article  CAS  Google Scholar 

  4. DeLeo, F. R. & Chambers, H. F. Reemergence of antibiotic-resistant Staphylococcus aureus in the genomics era. J. Clin. Invest. 119, 2464–2474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McCarthy, A. J. & Lindsay, J. A. Genetic variation in Staphylococcus aureus surface and immune evasion genes is lineage associated: implications for vaccine design and host–pathogen interactions. BMC Microbiol. 10, 173 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Heilbronner, S. et al. Genome sequence of Staphylococcus lugdunensis N920143 allows identification of putative colonization and virulence factors. FEMS Microbiol. Lett. 322, 60–67 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Bowden, M. G. et al. Identification and preliminary characterization of cell-wall-anchored proteins of Staphylococcus epidermidis. Microbiology 151, 1453–1464 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Hammer, N. D. & Skaar, E. P. Molecular mechanisms of Staphylococcus aureus iron acquisition. Annu. Rev. Microbiol. 65, 129–147 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Mazmanian, S. K. et al. Passage of heme–iron across the envelope of Staphylococcus aureus. Science 299, 906–909 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. McAleese, F. M., Walsh, E. J., Sieprawska, M., Potempa, J. & Foster, T. J. Loss of clumping factor B fibrinogen binding activity by Staphylococcus aureus involves cessation of transcription, shedding and cleavage by metalloprotease. J. Biol. Chem. 276, 29969–29978 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Bischoff, M. et al. Microarray-based analysis of the Staphylococcus aureus σB regulon. J. Bacteriol. 186, 4085–4099 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Patti, J. M., Allen, B. L., McGavin, M. J. & Hook, M. MSCRAMM-mediated adherence of microorganisms to host tissues. Annu. Rev. Microbiol. 48, 585–617 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Deivanayagam, C. C. et al. A novel variant of the immunoglobulin fold in surface adhesins of Staphylococcus aureus: crystal structure of the fibrinogen-binding MSCRAMM, clumping factor A. EMBO J. 21, 6660–6672 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bannoehr, J. et al. Genomic and surface proteomic analysis of the canine pathogen Staphylococcus pseudintermedius reveals proteins that mediate adherence to the extracellular matrix. Infect. Immun. 79, 3074–3086 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arrecubieta, C., Lee, M. H., Macey, A., Foster, T. J. & Lowy, F. D. SdrF, a Staphylococcus epidermidis surface protein, binds type I collagen. J. Biol. Chem. 282, 18767–18776 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Ponnuraj, K. et al. A “dock, lock, and latch” structural model for a staphylococcal adhesin binding to fibrinogen. Cell 115, 217–228 (2003). This paper provides the first description of the DLL mechanism for MSCRAMM ligand binding.

    Article  CAS  PubMed  Google Scholar 

  17. Rich, R. L. et al. Ace is a collagen-binding MSCRAMM from Enterococcus faecalis. J. Biol. Chem. 274, 26939–26945 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Nallapareddy, S. R., Weinstock, G. M. & Murray, B. E. Clinical isolates of Enterococcus faecium exhibit strain-specific collagen binding mediated by Acm, a new member of the MSCRAMM family. Mol. Microbiol. 47, 1733–1747 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Seo, H. S., Mu, R., Kim, B. J., Doran, K. S. & Sullam, P. M. Binding of glycoprotein Srr1 of Streptococcus agalactiae to fibrinogen promotes attachment to brain endothelium and the development of meningitis. PLoS Pathog. 8, e1002947 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lannergard, J., Frykberg, L. & Guss, B. CNE, a collagen-binding protein of Streptococcus equi. FEMS Microbiol. Lett. 222, 69–74 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Josefsson, E. et al. Three new members of the serine-aspartate repeat protein multigene family of Staphylococcus aureus. Microbiology 144, 3387–3395 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Josefsson, E., O'Connell, D., Foster, T. J., Durussel, I. & Cox, J. A. The binding of calcium to the B-repeat segment of SdrD, a cell surface protein of Staphylococcus aureus. J. Biol. Chem. 273, 31145–31152 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Zong, Y. et al. A 'Collagen Hug' model for Staphylococcus aureus CNA binding to collagen. EMBO J. 24, 4224–4236 (2005). This is the first report of the binding of the MSCRAMM Cna to collagen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Deivanayagam, C. C. et al. Novel fold and assembly of the repetitive B region of the Staphylococcus aureus collagen-binding surface protein. Structure 8, 67–78 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Xu, Y., Liang, X., Chen, Y., Koehler, T. M. & Hook, M. Identification and biochemical characterization of two novel collagen binding MSCRAMMs of Bacillus anthracis. J. Biol. Chem. 279, 51760–51768 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Cassat, J. E. & Skaar, E. P. Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity. Semin. Immunopathol. 34, 215–235 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Grigg, J. C., Ukpabi, G., Gaudin, C. F. & Murphy, M. E. Structural biology of heme binding in the Staphylococcus aureus Isd system. J. Inorg. Biochem. 104, 341–348 (2010). This is an excellent review of NEAT motif structures and ligand-binding mechanisms.

    Article  CAS  PubMed  Google Scholar 

  28. Deisenhofer, J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-Å resolution. Biochemistry 20, 2361–2370 (1981).

    Article  CAS  PubMed  Google Scholar 

  29. Cedergren, L., Andersson, R., Jansson, B., Uhlen, M. & Nilsson, B. Mutational analysis of the interaction between staphylococcal protein A and human IgG1. Protein Eng. 6, 441–448 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Smith, E. J. et al. The immune evasion protein Sbi of Staphylococcus aureus occurs both extracellularly and anchored to the cell envelope by binding lipoteichoic acid. Mol. Microbiol. 83, 789–804 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Burman, J. D. et al. Interaction of human complement with Sbi, a staphylococcal immunoglobulin-binding protein: indications of a novel mechanism of complement evasion by Staphylococcus aureus. J. Biol. Chem. 283, 17579–17593 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Lambris, J. D., Ricklin, D. & Geisbrecht, B. V. Complement evasion by human pathogens. Nature Rev. Microbiol. 6, 132–142 (2008).

    Article  CAS  Google Scholar 

  33. Conrady, D. G., Wilson, J. J. & Herr, A. B. Structural basis for Zn2+-dependent intercellular adhesion in staphylococcal biofilms. Proc. Natl Acad. Sci. USA 110, E202–E211 (2013). This paper confirms the G5–E repeat structure from reference 34 and proposes a mechanism for Aap-promoted (and SasG-promoted) biofilm formation.

    Article  CAS  PubMed  Google Scholar 

  34. Gruszka, D. T. et al. Staphylococcal biofilm-forming protein has a contiguous rod-like structure. Proc. Natl Acad. Sci. USA 109, E1011–E1018 (2012). This study provides the first description of the structure of the G5–E repeats of SasG that are involved in fibril formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Borgia, M. B. et al. Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. Nature 474, 662–665 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rohde, H. et al. Induction of Staphylococcus epidermidis biofilm formation via proteolytic processing of the accumulation-associated protein by staphylococcal and host proteases. Mol. Microbiol. 55, 1883–1895 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Geoghegan, J. A. et al. Role of surface protein SasG in biofilm formation by Staphylococcus aureus. J. Bacteriol. 192, 5663–5673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Silverman, G. J. & Goodyear, C. S. Confounding B-cell defences: lessons from a staphylococcal superantigen. Nature Rev. Immunol. 6, 465–475 (2006). This is a review of the role of protein A as a B cell superantigen.

    Article  CAS  Google Scholar 

  39. Ganesh, V. K. et al. Structural and biochemical characterization of Staphylococcus aureus clumping factor B/ligand interactions. J. Biol. Chem. 286, 25963–25972 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hair, P. S., Ward, M. D., Semmes, O. J., Foster, T. J. & Cunnion, K. M. Staphylococcus aureus clumping factor A binds to complement regulator factor I and increases factor I cleavage of C3b. J. Infect. Dis. 198, 125–133 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Mulcahy, M. E. et al. Nasal colonisation by Staphylococcus aureus depends upon clumping factor B binding to the squamous epithelial cell envelope protein loricrin. PLoS Pathog. 8, e1003092 (2012). This study uses knockout mice to show the in vivo significance of the binding of ClfB to loricrin by the DLL mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Walsh, E. J., Miajlovic, H., Gorkun, O. V. & Foster, T. J. Identification of the Staphylococcus aureus MSCRAMM clumping factor B (ClfB) binding site in the αC-domain of human fibrinogen. Microbiology 154, 550–558 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Walsh, E. J., O'Brien, L. M., Liang, X., Hook, M. & Foster, T. J. Clumping factor B, a fibrinogen-binding MSCRAMM (microbial surface components recognizing adhesive matrix molecules) adhesin of Staphylococcus aureus, also binds to the tail region of type I cytokeratin 10. J. Biol. Chem. 279, 50691–50699 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Xiang, H. et al. Crystal structures reveal the multi-ligand binding mechanism of Staphylococcus aureus ClfB. PLoS Pathog. 8, e1002751 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Keane, F. M. et al. Fibrinogen and elastin bind to the same region within the A domain of fibronectin binding protein A, an MSCRAMM of Staphylococcus aureus. Mol. Microbiol. 63, 711–723 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Falkow, S. Molecular Koch's postulates applied to microbial pathogenicity. Rev. Infect. Dis. 10 (Suppl. 2), S274–S276 (1988).

    Article  PubMed  Google Scholar 

  47. O'Brien, L. M., Walsh, E. J., Massey, R. C., Peacock, S. J. & Foster, T. J. Staphylococcus aureus clumping factor B (ClfB) promotes adherence to human type I cytokeratin 10: implications for nasal colonization. Cell. Microbiol. 4, 759–770 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Que, Y. A. et al. Fibrinogen and fibronectin binding cooperate for valve infection and invasion in Staphylococcus aureus experimental endocarditis. J. Exp. Med. 201, 1627–1635 (2005). This study uses expression of Fnb proteins and ClfA in Lactococcus lactis to show the role of their binding to fibrinogen and fibronectin in the pathogenesis of endocarditis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sinha, B. et al. Heterologously expressed Staphylococcus aureus fibronectin-binding proteins are sufficient for invasion of host cells. Infect. Immun. 68, 6871–6878 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Monk, I. R., Shah, I. M., Xu, M., Tan, M. W. & Foster, T. J. Transforming the untransformable: application of direct transformation to manipulate genetically Staphylococcus aureus and Staphylococcus epidermidis. MBio 3 e00277-11 (2012). This paper shows the evasion of the major restriction barrier to DNA transfer and provides a description of an improved vector for genetic manipulation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Monk, I. R. & Foster, T. J. Genetic manipulation of Staphylococci — breaking through the barrier. Front. Cell Infect. Microbiol. 2, 49 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Roberts, G. A. et al. Impact of target site distribution for Type I restriction enzymes on the evolution of methicillin-resistant Staphylococcus aureus (MRSA) populations. Nucleic Acids Res. 41, 7472–7484 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Davis, S. L., Gurusiddappa, S., McCrea, K. W., Perkins, S. & Hook, M. SdrG, a fibrinogen-binding bacterial adhesin of the microbial surface components recognizing adhesive matrix molecules subfamily from Staphylococcus epidermidis, targets the thrombin cleavage site in the Bβ chain. J. Biol. Chem. 276, 27799–27805 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Pishchany, G. et al. Specificity for human hemoglobin enhances Staphylococcus aureus infection. Cell Host Microbe 8, 544–550 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Patel, A. H., Nowlan, P., Weavers, E. D. & Foster, T. Virulence of protein A-deficient and α-toxin-deficient mutants of Staphylococcus aureus isolated by allele replacement. Infect. Immun. 55, 3103–3110 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kuypers, J. M. & Proctor, R. A. Reduced adherence to traumatized rat heart valves by a low-fibronectin-binding mutant of Staphylococcus aureus. Infect. Immun. 57, 2306–2312 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Patti, J. M. et al. The Staphylococcus aureus collagen adhesin is a virulence determinant in experimental septic arthritis. Infect. Immun. 62, 152–161 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rhem, M. N. et al. The collagen-binding adhesin is a virulence factor in Staphylococcus aureus keratitis. Infect. Immun. 68, 3776–3779 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cheng, A. G. et al. Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues. FASEB J. 23, 3393–3404 (2009). This paper provides a systematic analysis of the roles of S. aureus surface proteins in the pathogenesis of sepsis and abscess formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Grundmeier, M. et al. Truncation of fibronectin-binding proteins in Staphylococcus aureus strain Newman leads to deficient adherence and host cell invasion due to loss of the cell wall anchor function. Infect. Immun. 72, 7155–7163 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brouillette, E., Grondin, G., Shkreta, L., Lacasse, P. & Talbot, B. G. In vivo and in vitro demonstration that Staphylococcus aureus is an intracellular pathogen in the presence or absence of fibronectin-binding proteins. Microb. Pathog. 35, 159–168 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Palmqvist, N., Foster, T., Fitzgerald, J. R., Josefsson, E. & Tarkowski, A. Fibronectin-binding proteins and fibrinogen-binding clumping factors play distinct roles in staphylococcal arthritis and systemic inflammation. J. Infect. Dis. 191, 791–798 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Li, M. et al. MRSA epidemic linked to a quickly spreading colonization and virulence determinant. Nature Med. 18, 816–819 (2012). This paper shows that a novel CWA protein is associated with increased colonization by, and virulence of, an epidemic MRSA strain.

    Article  CAS  PubMed  Google Scholar 

  64. Lower, S. K. et al. Polymorphisms in fibronectin binding protein A of Staphylococcus aureus are associated with infection of cardiovascular devices. Proc. Natl Acad. Sci. USA 108, 18372–18377 (2011). This study shows that S. aureus bacteraemia isolates that infect cardiac devices have a higher affinity for fibronectin than those that only cause bacteraemia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kluytmans, J., van Belkum, A. & Verbrugh, H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin. Microbiol. Rev. 10, 505–520 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Johannessen, M., Sollid, J. E. & Hanssen, A. M. Host- and microbe determinants that may influence the success of S. aureus colonization. Front. Cell. Infect. Microbiol. 2, 56 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Edwards, A. M., Massey, R. C. & Clarke, S. R. Molecular mechanisms of Staphylococcus aureus nasopharyngeal colonization. Mol. Oral Microbiol. 27, 1–10 (2012). This is an excellent review of nasal colonization.

    Article  CAS  PubMed  Google Scholar 

  68. Burian, M. et al. Temporal expression of adhesion factors and activity of global regulators during establishment of Staphylococcus aureus nasal colonization. J. Infect. Dis. 201, 1414–1421 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Schaffer, A. C. et al. Immunization with Staphylococcus aureus clumping factor B, a major determinant in nasal carriage, reduces nasal colonization in a murine model. Infect. Immun. 74, 2145–2153 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Clarke, S. R. et al. Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. J. Infect. Dis. 193, 1098–1108 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Wertheim, H. F. et al. Key role for clumping factor B in Staphylococcus aureus nasal colonization of humans. PLoS Med. 5, e17 (2008). This study used experimental human nasal colonization with a genetically manipulated strain to show the importance of ClfB.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Clarke, S. R. et al. Iron-regulated surface determinant protein A mediates adhesion of Staphylococcus aureus to human corneocyte envelope proteins. Infect. Immun. 77, 2408–2416 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Corrigan, R. M., Miajlovic, H. & Foster, T. J. Surface proteins that promote adherence of Staphylococcus aureus to human desquamated nasal epithelial cells. BMC Microbiol. 9, 22 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Corrigan, R. M., Rigby, D., Handley, P. & Foster, T. J. The role of Staphylococcus aureus surface protein SasG in adherence and biofilm formation. Microbiology 153, 2435–2446 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Thwaites, G. E. & Gant, V. Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus? Nature Rev. Microbiol. 9, 215–222 (2011).

    Article  CAS  Google Scholar 

  76. Sendi, P. & Proctor, R. A. Staphylococcus aureus as an intracellular pathogen: the role of small colony variants. Trends Microbiol. 17, 54–58 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Sinha, B. et al. Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin α5β1. Cell. Microbiol. 1, 101–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Peacock, S. J., Foster, T. J., Cameron, B. J. & Berendt, A. R. Bacterial fibronectin-binding proteins and endothelial cell surface fibronectin mediate adherence of Staphylococcus aureus to resting human endothelial cells. Microbiology 145, 3477–3486 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Dziewanowska, K. et al. Fibronectin binding protein and host cell tyrosine kinase are required for internalization of Staphylococcus aureus by epithelial cells. Infect. Immun. 67, 4673–4678 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Schwarz-Linek, U. et al. Pathogenic bacteria attach to human fibronectin through a tandem β-zipper. Nature 423, 177–181 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Casolini, F. et al. Antibody response to fibronectin-binding adhesin FnbpA in patients with Staphylococcus aureus infections. Infect. Immun. 66, 5433–5442 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Edwards, A. M., Potts, J. R., Josefsson, E. & Massey, R. C. Staphylococcus aureus host cell invasion and virulence in sepsis is facilitated by the multiple repeats within FnBPA. PLoS Pathog. 6, e1000964 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Schwarz-Linek, U., Hook, M. & Potts, J. R. Fibronectin-binding proteins of Gram-positive cocci. Microbes Infect. 8, 2291–2298 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Schwarz-Linek, U., Hook, M. & Potts, J. R. The molecular basis of fibronectin-mediated bacterial adherence to host cells. Mol. Microbiol. 52, 631–641 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Zapotoczna, M., Jevnikar, Z., Miajlovic, H., Kos, J. & Foster, T. J. Iron-regulated surface determinant B (IsdB) promotes Staphylococcus aureus adherence to and internalization by non-phagocytic human cells. Cell. Microbiol. 15, 1026–1041 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Smith, E. J., Visai, L., Kerrigan, S. W., Speziale, P. & Foster, T. J. The Sbi protein is a multifunctional immune evasion factor of Staphylococcus aureus. Infect. Immun. 79, 3801–3809 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Palmqvist, N., Foster, T., Tarkowski, A. & Josefsson, E. Protein A is a virulence factor in Staphylococcus aureus arthritis and septic death. Microb. Pathog. 33, 239–249 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Hair, P. S. et al. Clumping factor A interaction with complement factor I increases C3b cleavage on the bacterial surface of Staphylococcus aureus and decreases complement-mediated phagocytosis. Infect. Immun. 78, 1717–1727 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sharp, J. A. et al. Staphylococcus aureus surface protein SdrE binds complement regulator factor H as an immune evasion tactic. PLoS ONE 7, e38407 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kang, M. et al. Collagen-binding microbial surface components recognizing adhesive matrix molecule (MSCRAMM) of Gram-positive bacteria inhibit complement activation via the classical pathway. J. Biol. Chem. 288, 20520–20531 (2013). This report provides the mechanistic basis of a surface protein that disrupts complement fixation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Josefsson, E., Hartford, O., O'Brien, L., Patti, J. M. & Foster, T. Protection against experimental Staphylococcus aureus arthritis by vaccination with clumping factor A, a novel virulence determinant. J. Infect. Dis. 184, 1572–1580 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Flick, M. J. et al. Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia. Blood 121, 1783–1794 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gomez, M. I. et al. Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nature Med. 10, 842–848 (2004). This study shows the pro-inflammatory effect of protein A in vitro and in vivo in the pathogenesis of pneumonia and definines TNFR1 as a new ligand for protein A.

    Article  CAS  PubMed  Google Scholar 

  94. Wilke, G. A. & Bubeck Wardenburg, J. Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus αhemolysin-mediated cellular injury. Proc. Natl Acad. Sci. USA 107, 13473–13478 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Inoshima, I. et al. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nature Med. 17, 1310–1314 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Gomez, M. I., Seaghdha, M. O. & Prince, A. S. Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling. EMBO J. 26, 701–709 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Martin, F. J. et al. Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A. J. Clin. Invest. 119, 1931–1939 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. O'Gara, J. P. & Humphreys, H. Staphylococcus epidermidis biofilms: importance and implications. J. Med. Microbiol. 50, 582–587 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Zimmerli, W., Trampuz, A. & Ochsner, P. E. Prosthetic-joint infections. N. Engl. J. Med. 351, 1645–1654 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Otto, M. Staphylococcus epidermidis — the 'accidental' pathogen. Nature Rev. Microbiol. 7, 555–567 (2009).

    Article  CAS  Google Scholar 

  101. Otto, M. Staphylococcal biofilms. Curr. Top. Microbiol. Immunol. 322, 207–228 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Heilmann, C. et al. Molecular basis of intercellular adhesion in the biofilm-forming Staphylococcus epidermidis. Mol. Microbiol. 20, 1083–1091 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. O'Neill, E. et al. A novel Staphylococcus aureus biofilm phenotype mediated by the fibronectin-binding proteins, FnBPA and FnBPB. J. Bacteriol. 190, 3835–3850 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Geoghegan, J. A., Monk, I. R., O'Gara, J. P. & Foster, T. J. Subdomains N2N3 of fibronectin binding protein A mediate Staphylococcus aureus biofilm formation and adherence to fibrinogen using distinct mechanisms. J. Bacteriol. 195, 2675–2683 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lauderdale, K. J., Boles, B. R., Cheung, A. L. & Horswill, A. R. Interconnections between Sigma B, agr, and proteolytic activity in Staphylococcus aureus biofilm maturation. Infect. Immun. 77, 1623–1635 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cucarella, C. et al. Bap, a Staphylococcus aureus surface protein involved in biofilm formation. J. Bacteriol. 183, 2888–2896 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Abraham, N. M. & Jefferson, K. K. Staphylococcus aureus clumping factor B mediates biofilm formation in the absence of calcium. Microbiology 158, 1504–1512 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schroeder, K. et al. Molecular characterization of a novel Staphylococcus aureus surface protein (SasC) involved in cell aggregation and biofilm accumulation. PLoS ONE 4, e7567 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Merino, N. et al. Protein A-mediated multicellular behavior in Staphylococcus aureus. J. Bacteriol. 191, 832–843 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Barbu, E. M. et al. β-neurexin is a ligand for the Staphylococcus aureus MSCRAMM SdrC. PLoS Pathog. 6, e1000726 (2010). This paper uses phage display to identify a novel ligand for an MSCRAMM.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Loughman, A. et al. Sequence diversity in the A domain of Staphylococcus aureus fibronectin-binding protein A. BMC Microbiol. 8, 74 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Burke, F. M., McCormack, N., Rindi, S., Speziale, P. & Foster, T. J. Fibronectin-binding protein B variation in Staphylococcus aureus. BMC Microbiol. 10, 160 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Nilsson, I. M., Patti, J. M., Bremell, T., Hook, M. & Tarkowski, A. Vaccination with a recombinant fragment of collagen adhesin provides protection against Staphylococcus aureus-mediated septic death. J. Clin. Invest. 101, 2640–2649 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Stranger-Jones, Y. K., Bae, T. & Schneewind, O. Vaccine assembly from surface proteins of Staphylococcus aureus. Proc. Natl Acad. Sci. USA 103, 16942–16947 (2006). This report provides a systematic analysis of the protective efficacy of recombinant CWA proteins as antigens and shows that a combination of four antigens offers better protection than each antigen alone.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fowler, V. G. et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA 309, 1368–1378 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Bagnoli, F., Bertholet, S. & Grandi, G. Inferring reasons for the failure of Staphylococcus aureus vaccines in clinical trials. Front. Cell. Infect. Microbiol. 2, 16 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Anderson, A. S. et al. Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors. Hum. Vaccin. Immunother. 8, 1585–1594 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jansen, K. U., Girgenti, D. Q., Scully, I. L. & Anderson, A. S. Vaccine review: “Staphyloccocus aureus vaccines: problems and prospects”. Vaccine 31, 2723–2730 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Josefsson, E., Higgins, J., Foster, T. J. & Tarkowski, A. Fibrinogen binding sites P336 and Y338 of clumping factor A are crucial for Staphylococcus aureus virulence. PLoS ONE 3, e2206 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Kim, H. K., Cheng, A. G., Kim, H. Y., Missiakas, D. M. & Schneewind, O. Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice. J. Exp. Med. 207, 1863–1870 (2010). This paper shows that recombinant protein A that lacks the ability to bind to IgG or IgM is a better immunogen than wild-type protein A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ross, C. L. et al. Targeted protein engineering provides insights into binding mechanism and affinities of bacterial collagen adhesins. J. Biol. Chem. 287, 34856–34865 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ventura, C. L. et al. Identification of a novel Staphylococcus aureus two-component leukotoxin using cell surface proteomics. PLoS ONE 5, e11634 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ganesh, V. K. et al. A structural model of the Staphylococcus aureus ClfA-fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics. PLoS Pathog. 4, e1000226 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Vazquez, V. et al. Fibrinogen is a ligand for the Staphylococcus aureus microbial surface components recognizing adhesive matrix molecules (MSCRAMM) bone sialoprotein-binding protein (Bbp). J. Biol. Chem. 286, 29797–29805 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Burke, F. M., Di Poto, A., Speziale, P. & Foster, T. J. The A domain of fibronectin-binding protein B of Staphylococcus aureus contains a novel fibronectin binding site. FEBS J. 278, 2359–2371 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Clarke, S. R., Wiltshire, M. D. & Foster, S. J. IsdA of Staphylococcus aureus is a broad spectrum, iron-regulated adhesin. Mol. Microbiol. 51, 1509–1519 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Clarke, S. R. & Foster, S. J. IsdA protects Staphylococcus aureus against the bactericidal protease activity of apolactoferrin. Infect. Immun. 76, 1518–1526 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Clarke, S. R. et al. The Staphylococcus aureus surface protein IsdA mediates resistance to innate defenses of human skin. Cell Host Microbe 1, 199–212 (2007). This paper shows that IsdA is a multifunctional surface protein that is involved in iron acquisition, nasal carriage and the promotion of survival on skin by conferring resistance to bactericidal lipids.

    Article  CAS  PubMed  Google Scholar 

  129. Pilpa, R. M. et al. Functionally distinct NEAT (NEAr Transporter) domains within the Staphylococcus aureus IsdH/HarA protein extract heme from methemoglobin. J. Biol. Chem. 284, 1166–1176 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Visai, L. et al. Immune evasion by Staphylococcus aureus conferred by iron-regulated surface determinant protein IsdH. Microbiology 155, 667–679 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Graille, M. et al. Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody: structural basis for recognition of B-cell receptors and superantigen activity. Proc. Natl Acad. Sci. USA 97, 5399–5404 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Silverman, G. J. et al. A B-cell superantigen that targets B-1 lymphocytes. Curr. Top. Microbiol. Immunol. 252, 251–263 (2000).

    CAS  PubMed  Google Scholar 

  133. Gomez, M. I., O'Seaghdha, M., Magargee, M., Foster, T. J. & Prince, A. S. Staphylococcus aureus protein A activates TNFR1 signaling through conserved IgG binding domains. J. Biol. Chem. 281, 20190–20196 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. O'Seaghdha, M. et al. Staphylococcus aureus protein A binding to von Willebrand factor A1 domain is mediated by conserved IgG binding regions. FEBS J. 273, 4831–4841 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Roche, F. M., Meehan, M. & Foster, T. J. The Staphylococcus aureus surface protein SasG and its homologues promote bacterial adherence to human desquamated nasal epithelial cells. Microbiology 149, 2759–2767 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. Savolainen, K. et al. Expression of pls, a gene closely associated with the mecA gene of methicillin-resistant Staphylococcus aureus, prevents bacterial adhesion in vitro. Infect. Immun. 69, 3013–3020 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Thammavongsa, V., Schneewind, O. & Missiakas, D. M. Enzymatic properties of Staphylococcus aureus adenosine synthase (AdsA). BMC Biochem. 12, 56 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Thammavongsa, V., Kern, J. W., Missiakas, D. M. & Schneewind, O. Staphylococcus aureus synthesizes adenosine to escape host immune responses. J. Exp. Med. 206, 2417–2427 (2009). This paper provides a description of a novel function for the surface protein S. aureus adenosine synthase A (AdsA) in innate immune evasion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Siboo, I. R., Chambers, H. F. & Sullam, P. M. Role of SraP, a serine-rich surface protein of Staphylococcus aureus, in binding to human platelets. Infect. Immun. 73, 2273–2280 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kukita, K. et al. Staphylococcus aureus SasA. is responsible for binding to salivary agglutinin, gp340, derived from human saliva. Infect. Immun. 81, 1870–1879 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Roche, F. M. et al. Characterization of novel LPXTG-containing proteins of Staphylococcus aureus identified from genome sequences. Microbiology 149, 643–654 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Rosander, A., Guss, B. & Pringle, M. An IgG-binding protein A homolog in Staphylococcus hyicus. Vet. Microbiol. 149, 273–276 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Moreillon, P. et al. Role of Staphylococcus aureus coagulase and clumping factor in pathogenesis of experimental endocarditis. Infect. Immun. 63, 4738–4743 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Entenza, J. M. et al. Contribution of clumping factor B to pathogenesis of experimental endocarditis due to Staphylococcus aureus. Infect. Immun. 68, 5443–5446 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Vergara-Irigaray, M. et al. Relevant role of fibronectin-binding proteins in Staphylococcus aureus biofilm-associated foreign-body infections. Infect. Immun. 77, 3978–3991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Arrecubieta, C. et al. The role of Staphylococcus aureus adhesins in the pathogenesis of ventricular assist device-related infections. J. Infect. Dis. 193, 1109–1119 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Valle, J. et al. Bap, a biofilm matrix protein of Staphylococcus aureus prevents cellular internalization through binding to GP96 host receptor. PLoS Pathog. 8, e1002843 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

T.J.F. would like to acknowledge Science Foundation Ireland Programme Investigator grant 08/IN1/B1845. M.H. would like to acknowledge NIH grant AI 20624. The authors would like to thank D. Ravirajan for help with the on-line movie.

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Glossary

Coagulase-negative staphylococci

Staphylococcus spp. (other than Staphylococcus aureus) that do not express coagulase and are less virulent.

Extracellular matrix

The extracellular components of tissue that often provide structural support for cells.

Fibronectin

A high-molecular-weight dimeric glycoprotein that is found in serum and in the extracellular matrix (ECM). It binds to integrins and to other components of the ECM.

Oxidative burst

A respiratory burst that is produced by phagocytic cells. NADPH oxidase causes the rapid release of reactive oxygen species (superoxide and hydrogen peroxide).

Complement

Proteins in serum that are activated by the presence of foreign antigens; a proteolytic cascade leads to the formation of the neutrophil opsosin C3b and the chemoattractant peptides C3a and C5a.

Apo form

The form of a protein without bound ligand.

Elastin

An elastic protein in connective tissue. It allows tissue to regain shape by stretching or contracting.

Isogenic

A term used to describe strains that are characterized by identical genes.

Squamous epithelium

The most superficial layer of stratified epithelium; it consists of flat, scale-like squamous epithelial cells (known as squames) that have a cornified envelope composed of proteins.

Ω loops

Strings of glycine and serine residues in keratin 10 and loricrin, flanked by hydrophobic amino acids. Modelling suggests the formation of structures that are shaped like the Greek capital letter Ω.

Fc regions

Fragment crystallizable regions at the tail of antibodies; they react with specific receptors on neutrophils and with the complement protein C1q to trigger the classical pathway of complement fixation.

Classical pathway

One of three pathways for activating complement fixation. Requires clustered IgG molecules with their Fc regions pointing outwards to attract the hexameric complement protein C1q.

Opsonin

A protein (antibody or complement protein) that enhances phagocytosis by neutrophils.

α-toxin

A β-barrel pore-forming cytolysin that is secreted as a monomer and forms a heptamer in the membranes of susceptible cells; it is an important virulence factor.

Tight junctions

Areas of close contact between the membranes of epithelial and endothelial cells; they are connected to the actin cytoskeleton.

Phage-display technology

Bacteriophages that display libraries of peptides that are incorporated into capsid proteins. Individual particles that bind to ligands are enriched by 'panning'. The peptide sequences are identified by DNA sequencing.

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Foster, T., Geoghegan, J., Ganesh, V. et al. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol 12, 49–62 (2014). https://doi.org/10.1038/nrmicro3161

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