Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Staphylococcal manipulation of host immune responses

Nature Reviews Microbiology volume 13, pages 529–543 (2015)Cite this article

Subjects

Key Points

  • Staphylococcus aureus evades innate and adaptive immune responses to cause localized or systemic infections in humans. Because the development of protective immunity is prevented, S. aureus infections reoccur even with antibiotic or surgical therapy.

  • Mechanisms have been revealed whereby products secreted by S. aureus interfere with neutrophil chemotaxis, complement activation, opsonization and phagocytic killing of bacteria. Immune evasion determinants can interact with host factors from humans, but not with counterparts from other vertebrates, which presents a challenge for the development of animal models.

  • The hallmark of S. aureus is the secretion of coagulases that associate with prothrombin to generate fibrin clots. Through the fibrinogen and fibrin binding attributes of staphylococcal surface proteins, the pathogen shields itself from host phagocytes, which is a prerequisite for abscess lesion formation in infected tissues. Macrophage access to these lesions is restricted by staphylococcal-induced degradation of neutrophil extracellular traps (NETs).

  • Staphylococcal protein A (SpA) crosslinks B cell receptors and triggers proliferative expansion of VH3+ B cells and the secretion of antibodies that fail to recognize S. aureus antigens. SpA blocks host antibody responses that are required for the establishment of protective immunity.

  • T cell superantigens crosslink major histocompatibility class II molecules of antigen-presenting cells with the T cell receptor, promoting lymphocyte proliferation, anergy and the release of cytokines (a cytokine storm). Superantigens vary between S. aureus strains and activate distinct subsets of Vβ chain T cell receptors, endowing staphylococcal isolates with unique T cell-avoidance attributes.

  • Genome sequencing of S. aureus isolates from humans or domesticated animals revealed that only some immune evasion genes are conserved among all strains. Even conserved genes display sequence polymorphisms, which presents a formidable challenge for the design of S. aureus vaccines. Panoplies of immune evasion factors endow staphylococcal strains with unique virulence attributes and with the ability for epidemic spread.

Abstract

Staphylococcus aureus, a bacterial commensal of the human nares and skin, is a frequent cause of soft tissue and bloodstream infections. A hallmark of staphylococcal infections is their frequent recurrence, even when treated with antibiotics and surgical intervention, which demonstrates the bacterium's ability to manipulate innate and adaptive immune responses. In this Review, we highlight how S. aureus virulence factors inhibit complement activation, block and destroy phagocytic cells and modify host B cell and T cell responses, and we discuss how these insights might be useful for the development of novel therapies against infections with antibiotic resistant strains such as methicillin-resistant S. aureus.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Staphylococcus aureus interference with chemotaxis, complement and killing by phagocytes.
Figure 2: Staphylococcus aureus agglutination with fibrin provides protection against phagocytes.
Figure 3: Staphylococcus aureus AdsA perturbs adenosine and deoxyadenosine signalling.
Figure 4: Staphylococcus aureus manipulates B cell and T cell responses.

Similar content being viewed by others

References

  1. van Belkum, A. et al. Co-evolutionary aspects of human colonisation and infection by Staphylococcus aureus. Infect. Genet. Evol. 9, 32–47 (2009).

    CAS  PubMed  Google Scholar 

  2. David, M. Z. & Daum, R. S. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin. Microbiol. Rev. 23, 616–687 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kallen, A. J. et al. Health care-associated invasive MRSA infections, 2005–2008. JAMA 304, 641–648 (2010).

    CAS  PubMed  Google Scholar 

  4. Spaan, A. N., Surewaard, B. G. J., Nijland, R. & van Strijp, J. A. G. Neutrophils versus Staphylococcus aureus: a biological tug of war. Annu. Rev. Microbiol. 67, 629–650 (2013). This excellent review summarizes the molecular events that occur during encounters between neutrophils and staphylococci.

    CAS  PubMed  Google Scholar 

  5. Curnutte, J. T., Whitten, D. M. & Babior, B. M. Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N. Engl. J. Med. 290, 593–597 (1974).

    CAS  PubMed  Google Scholar 

  6. Casanova, J. L., Holland, S. M. & Notarangelo, L. D. Inborn errors of human JAKs and STATs. Immunity 36, 515–528 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Maródi, L. et al. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J. Allergy Clin. Immunol. 130, 1019–1027 (2012).

    PubMed  PubMed Central  Google Scholar 

  8. Chemaly, R. F. et al. Characteristics and outcomes of methicillin-resistant Staphylococcus aureus surgical-site infections in patients with cancer: a case-control study. Ann. Surg. Oncol. 17, 1499–1506 (2010).

    PubMed  Google Scholar 

  9. Spaan, A. N. et al. The staphylococcal toxin panton-valentine leukocidin targets human c5a receptors. Cell Host Microbe 13, 584–594 (2013). This report describes the C5a receptor as the target of PVL, an important leukocidin secreted by some S. aureus strains.

    CAS  PubMed  Google Scholar 

  10. Williams, R. J. et al. Identification of a novel gene cluster encoding staphylococcal exotoxin-like proteins: characterization of the prototypic gene and its protein product, SET1. Infect. Immun. 68, 4407–4415 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Fitzgerald, J. R. et al. Genome diversification in Staphylococcus aureus: molecular evolution of a highly variable chromosomal region encoding the staphylococcal exotoxin-like family of proteins. Infect. Immun. 71, 2827–2838 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Arcus, V. L., Langley, R., Proft, T., Fraser, J. D. & Baker, E. N. The three-dimensional structure of a superantigen-like protein, SET3, from a pathogenicity island of the Staphylococcus aureus genome. J. Biol. Chem. 277, 32274–32281 (2002).

    CAS  PubMed  Google Scholar 

  13. McCarthy, A. J. & Lindsay, J. A. Staphylococcus aureus innate immune evasion is lineage-specific: a bioinformatics study. Infect. Genet. Evol. 19, 7–14 (2013). This report characterizes lineage-specific alleles and distribution of S. aureus immune evasion determinants.

    CAS  PubMed  Google Scholar 

  14. Bestebroer, J. et al. Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling. Blood 109, 2936–2943 (2007).

    CAS  PubMed  Google Scholar 

  15. Chung, M. C. et al. The crystal structure of staphylococcal superantigen-like protein 11 in complex with sialyl Lewis X reveals the mechanism for cell binding and immune inhibition. Mol. Microbiol. 66, 1342–1355 (2007).

    CAS  PubMed  Google Scholar 

  16. Bestebroer, J. et al. Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins. Blood 113, 328–337 (2009).

    CAS  PubMed  Google Scholar 

  17. de Haas, C. J. et al. Staphylococcal superantigen-like 5 activates platelets and supports platelet adhesion under flow conditions, which involves glycoprotein Ibα and αIIbβ3. J. Thromb. Haemost. 7, 1867–1874 (2009).

    CAS  PubMed  Google Scholar 

  18. Hu, H. et al. GPVI and GPIbα mediate staphylococcal superantigen-like protein 5 (SSL5) induced platelet activation and direct toward glycans as potential inhibitors. PLoS ONE 6, e19190 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Armstrong, P. C. et al. Staphylococcal superantigen-like protein 5 induces thrombotic and bleeding complications in vivo: inhibition by an anti-SSL5 antibody and the glycan bimosiamose. J. Thromb. Haemost. 10, 2607–2609 (2012).

    CAS  PubMed  Google Scholar 

  20. Itoh, S. et al. Staphylococcal superantigen-like protein 5 inhibits matrix metalloproteinase 9 from human neutrophils. Infect. Immun. 78, 3298–3305 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hermans, S. J. et al. Structural and functional properties of staphylococcal superantigen-like protein 4. Infect. Immun. 80, 4004–4013 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yokoyama, R. et al. Staphylococcal superantigen-like protein 3 binds to the Toll-like receptor 2 extracellular domain and inhibits cytokine production induced by Staphylococcus aureus, cell wall component, or lipopeptides in murine macrophages. Infect. Immun. 80, 2816–2825 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fevre, C. et al. Staphylococcus aureus proteins SSL6 and SElX interact with neutrophil receptors as identified using secretome phage display. Cell. Microbiol. 16, 1646–1665 (2014).

    CAS  PubMed  Google Scholar 

  24. Chavakis, T. et al. Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes. Nat. Med. 8, 687–693 (2002).

    CAS  PubMed  Google Scholar 

  25. Peschel, A. & Otto, M. Phenol-soluble modulins and staphylococcal infection. Nat. Rev. Microbiol. 11, 667–673 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kretschmer, D. et al. Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus. Cell Host Microbe 7, 463–473 (2010). This paper identifies formyl receptor 2 signalling as the target for S. aureus phenol-soluble modulins.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Forsman, H., Christenson, K., Bylund, J. & Dahlgren, C. Receptor-dependent and -independent immunomodulatory effects of phenol-soluble modulin peptides from Staphylococcus aureus on human neutrophils are abrogated through peptide inactivation by reactive oxygen species. Infect. Immun. 80, 1987–1995 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cheung, G. Y. et al. Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection. PLoS Pathog. 10, e1004298 (2014).

    PubMed  PubMed Central  Google Scholar 

  29. van Wamel, W. J., Rooijakkers, S. H., Ruyken, M., van Kessel, K. P. & van Strijp, J. A. The innate immune modulators staphylococcal complement inhibitor and chemotaxis inhibitory protein of Staphylococcus aureus are located on β-hemolysin-converting bacteriophages. J. Bacteriol. 188, 1310–1315 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. de Haas, C. J. et al. Chemotaxis inhibitory protein of Staphylococcus aureus, a bacterial antiinflammatory agent. J. Exp. Med. 199, 687–695 (2004). This report characterizes CHIPS as an inhbitor of chemotaxis and complement-mediated immune cell activation.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Postma, B. et al. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J. Immunol. 172, 6994–7001 (2004).

    CAS  PubMed  Google Scholar 

  32. Prat, C., Bestebroer, J., de Haas, C. J., van Strijp, J. A. & van Kessel, K. P. A new staphylococcal anti-inflammatory protein that antagonizes the formyl peptide receptor-like 1. J. Immunol. 177, 8017–8026 (2006).

    CAS  PubMed  Google Scholar 

  33. Prat, C. et al. A homolog of formyl peptide receptor-like 1 (FPRL1) inhibitor from Staphylococcus aureus (FPRL1 inhibitory protein) that inhibits FPRL1 and FPR. J. Immunol. 183, 6569–6578 (2009).

    CAS  PubMed  Google Scholar 

  34. Laarman, A. J. et al. Staphylococcus aureus staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis. EMBO J. 31, 3607–3619 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bubeck Wardenburg, J., Williams, W. A. & Missiakas, D. Host defenses against Staphylococcus aureus infection require recognition of bacterial lipoproteins. Proc. Natl Acad. Sci. USA 103, 13831–13836 (2006).

    PubMed  Google Scholar 

  36. Cheng, A. G. et al. Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues. FASEB J. 23, 3393–3404 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gros, P., Milder, F. J. & Janssen, B. J. Complement driven by conformational changes. Nat. Rev. Immunol. 8, 48–58 (2008).

    CAS  PubMed  Google Scholar 

  38. Laarman, A., Milder, F., van Strijp, J. A. & Rooijakkers, S. H. Complement inhibition by gram-positive pathogens: molecular mechanisms and therapeutic implications. J. Mol. Med. 88, 115–120 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. O'Riordan, K. & Lee, J. C. Staphylococcus aureus capsular polysaccharides. Clin. Microbiol. Rev. 17, 218–234 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Montgomery, C. P. et al. Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia. J. Infect. Dis. 198, 561–570 (2008).

    CAS  PubMed  Google Scholar 

  41. Laarman, A. J. et al. Staphylococcus aureus metalloprotease aureolysin cleaves complement C3 to mediate immune evasion. J. Immunol. 186, 6445–6453 (2011).

    CAS  PubMed  Google Scholar 

  42. Rooijakkers, S. H. et al. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat. Immunol. 6, 920–927 (2005). The paper discovers SCIN as an inhibitor of C3 convertases, blocking C3b deposition on staphylococcal surfaces.

    CAS  PubMed  Google Scholar 

  43. Jongerius, I. et al. Staphylococcal complement evasion by various convertase-blocking molecules. J. Exp. Med. 204, 2461–2471 (2007). This manuscript identifies SCIN-B, SCIN-C, Ecb and Efb as inhibitors of C3 and C5 convertases.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen, H. et al. Allosteric inhibition of complement function by a staphylococcal immune evasion protein. Proc. Natl Acad. Sci. USA 107, 17621–17626 (2010).

    CAS  PubMed  Google Scholar 

  45. Amdahl, H. et al. Staphylococcal Ecb protein and host complement regulator factor H enhance functions of each other in bacterial immune evasion. J. Immunol. 191, 1775–1184 (2013).

    CAS  PubMed  Google Scholar 

  46. Jongerius, I., Garcia, B. L., Geisbrecht, B. V., van Strijp, J. A. & Rooijakkers, S. H. Convertase inhibitory properties of staphylococcal extracellular complement-binding protein. J. Biol. Chem. 285, 14973–14979 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ko, Y. P. et al. Phagocytosis escape by a Staphylococcus aureus protein that connects complement and coagulation proteins at the bacterial surface. PLoS Pathog. 9, e1003816 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. Jongerius, I. et al. Staphylococcus aureus virulence is enhanced by secreted factors that block innate immune defenses. J. Innate Immun. 4, 301–311 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bestebroer, J. et al. Functional basis for complement evasion by staphylococcal superantigen-like 7. Cell. Microbiol. 12, 1506–1516 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Patel, D., Wines, B. D., Langley, R. J. & Fraser, J. D. Specificity of staphylococcal superantigen-like protein 10 toward human IgG1 Fc domain. J. Immunol. 184, 6283–6292 (2010).

    CAS  PubMed  Google Scholar 

  51. Itoh, S. et al. Staphylococcal superantigen-like protein 10 (SSL10) inhibits blood coagulation by binding to prothrombin and factor Xa via their γ-carboxyglutamic acid (Gla) domain. J. Biol. Chem. 288, 21569–21580 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, L., Jacobsson, K., Vasi, J., Lindberg, M. & Frykberg, L. A second IgG-binding protein in Staphylococcus aureus. Microbiology 144, 985–991 (1998).

    CAS  PubMed  Google Scholar 

  53. Kim, H. K. et al. Protein A-specific monoclonal antibodies and the prevention of Staphylococcus aureus disease in mice. Infect. Immun. 80, 3460–3470 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Haupt, K. et al. The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a tripartite complex with host complement Factor H and C3b. PloS Pathog. 4, e1000250 (2008). The manuscript explains the functional properties of Sbi-mediated immune evasion.

    PubMed  PubMed Central  Google Scholar 

  56. Parry, M. A. et al. The ternary microplasmin-staphylokinase-microplasmin complex is a proteinase-cofactor-substrate complex in action. Nat. Struct. Biol. 5, 917–923 (1998).

    CAS  PubMed  Google Scholar 

  57. Rooijakkers, S. H., van Wamel, W. J., Ruyken, M., van Kessel, K. P. & van Strijp, J. A. Anti-opsonic properties of staphylokinase. Microbes Infect. 7, 476–484 (2005).

    CAS  PubMed  Google Scholar 

  58. Jin, T. et al. Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism. J. Immunol. 172, 1169–1176 (2004).

    CAS  PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Bera, A., Herbert, S., Jakob, A., Vollmer, W. & Götz, F. Why are pathogenic staphylococci so lysozyme resistant? The peptidoglycan O-acetyltransferase OatA is the major determinant for lysozyme resistance of Staphylococcus aureus. Mol. Microbiol. 55, 778–787 (2005).

    CAS  PubMed  Google Scholar 

  61. Peschel, A. et al. Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J. Biol. Chem. 274, 8405–8410 (1999).

    CAS  PubMed  Google Scholar 

  62. Ernst, C. M. & Peschel, A. Broad-spectrum antimicrobial peptide resistance by MprF-mediated aminoacylation and flipping of phospholipids. Mol. Microbiol. 80, 290–299 (2011).

    CAS  PubMed  Google Scholar 

  63. Pelz, A. et al. Structure and biosynthesis of staphyloxanthin from Staphylococcus aureus. J. Biol. Chem. 280, 32493–32498 (2005).

    CAS  PubMed  Google Scholar 

  64. Liu, G. Y. et al. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202, 209–215 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Karavolos, M. H., Horsburgh, M. J., Ingham, E. & Foster, S. J. Role and regulation of the superoxide dismutases of Staphylococcus aureus. Microbiology 149, 2749–2758 (2003).

    CAS  PubMed  Google Scholar 

  66. Cosgrove, K. et al. Catalase (KatA) and alkyl hydroperoxide reductase (AhpC) have compensatory roles in peroxide stress resistance and are required for survival, persistence, and nasal colonization in Staphylococcus aureus. J. Bacteriol. 189, 1025–1035 (2007).

    CAS  PubMed  Google Scholar 

  67. Richardson, A. R., Libby, S. J. & Fang, F. C. A nitric oxide-inducible lactate dehydrogenase enables Staphylococcus aureus to resist innate immunity. Science 319, 1672–1676 (2008). A report on how staphylococcal metabolism diverts nitrosative stress and provides escape from phagocytic killing.

    CAS  PubMed  Google Scholar 

  68. Stapels, D. A. et al. Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors. Proc. Natl Acad. Sci. USA 111, 13187–13192 (2014). This paper shows that three secreted molecules of S. aureus — Eap, EapH1 and EapH2 — block neutrophil proteases to escape phagocytic killing.

    CAS  PubMed  Google Scholar 

  69. Wang, R. et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat. Med. 13, 1418–1420 (2007).

    Google Scholar 

  70. Surewaard, B. G. et al. Staphylococcal α-phenol soluble modulins contribute to neutrophil lysis after phagocytosis. Cell. Microbiol. 15, 1427–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Heuck, A. P., Tweten, R. K. & Johnson, A. E. β-barrel pore-forming toxins: intriguing dimorphic proteins. Biochemistry 40, 9065–9073 (2001).

    CAS  PubMed  Google Scholar 

  72. DeLeo, F. R. et al. Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. Proc. Natl Acad. Sci. USA 108, 18091–18096 (2011).

    CAS  PubMed  Google Scholar 

  73. Wilke, G. A. & Bubeck Wardenburg, J. Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin-mediated cellular injury. Proc. Natl Acad. Sci. USA 107, 13473–13478 (2010). The paper identifies ADAM10 as the receptor for staphylococcal α -haemolysin.

    CAS  PubMed  Google Scholar 

  74. Becker, R. E., Berube, B. J., Sampedro, G. R., Dedent, A. C. & Bubeck Wardenburg, J. Tissue-specific patterning of host innate immune responses by Staphylococcus aureus α-toxin. J. Innate Immun. 6, 619–631 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Bubeck Wardenburg, J. & Schneewind, O. Vaccine protection against Staphylococcus aureus pneumonia. J. Exp. Med. 205, 287–294 (2008).

    PubMed  Google Scholar 

  76. Bubeck Wardenburg, J., Palazzolo-Ballance, A. M., Otto, M., Schneewind, O. & DeLeo, F. R. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J. Infect. Dis. 198, 1166–1170 (2008).

    PubMed  Google Scholar 

  77. Powers, M. E., Kim, H. K., Wang, Y.-T. & Bubeck-Wardenburg, J. ADAM10 mediates vascular injury induced by Staphylococcus aureus α-hemolysin. J. Infect. Dis. 206, 352–356 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Miles, G., Movileanu, L. & Bayley, H. Subunit composition of a bicomponent toxin: staphylococcal leukocidin forms an octameric transmembrane pore. Protein Sci. 11, 894–902 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Alonzo, F. & Torres, V. J. The bicomponent pore-forming leucocidins of Staphylococcus aureus. Microbiol. Mol. Biol. Rev. 78, 199–230 (2014).

    PubMed  PubMed Central  Google Scholar 

  80. DuMont, A. L. et al. Staphylococcus aureus LukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1. Proc. Natl Acad. Sci. USA 110, 10794–10799 (2013).

    CAS  PubMed  Google Scholar 

  81. Malachowa, N., Kobayashi, S. D., Freedman, B., Dorward, D. W. & DeLeo, F. R. Staphylococcus aureus leukotoxin GH promotes formation of neutrophil extracellular traps. J. Immunol. 191, 6022–6029 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. DuMont, A. L. et al. Staphylococcus aureus elaborates leukocidin AB to mediate escape from within human neutrophils. Infect. Immun. 81, 1830–1841 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Malachowa, N. & DeLeo, F. R. Staphylococcus aureus survival in human blood. Virulence 2, 567–569 (2011). This manuscript identifies the receptors for staphylococcal γ -haemolysins AB and CB on immune cells.

    PubMed  PubMed Central  Google Scholar 

  84. Spaan, A. N. et al. The staphylococcal toxins γ-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors. Nat. Commun. 5, 5438 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Malachowa, N. et al. Global changes in Staphylococcus aureus gene expression in human blood. PLoS ONE 6, e18617 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Malachowa, N. et al. Staphylococcus aureus leukotoxin GH promotes inflammation. J. Infect. Dis. 206, 1185–1193 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Alonzo, F. et al. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature 493, 51–55 (2013). This paper implicated G protein-coupled receptors as the targets of leukocidins, which are β -PFTs that are secereted by S. aureus to subvert innate immune responses.

    PubMed  Google Scholar 

  88. Reyes-Robles, T. et al. Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. Cell Host Microbe 14, 453–459 (2013).

    CAS  PubMed  Google Scholar 

  89. Alonzo, F. et al. Staphylococcus aureus leucocidin ED contributes to systemic infection by targeting neutrophils and promoting bacterial growth in vivo. Mol. Microbiol. 83, 423–435 (2012).

    CAS  PubMed  Google Scholar 

  90. Panton, P. N. & Valentine, F. C. O. Staphylococcal toxin. Lancet 222, 506–508 (1932).

    Google Scholar 

  91. Gillet, Y. et al. Association between Staphylococcus aureus strains carrying gene for Panton–Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359, 753–759 (2002).

    CAS  PubMed  Google Scholar 

  92. Diep, B. A. et al. Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton–Valentine leukocidin-induced lung inflammation and injury. Proc. Natl Acad. Sci. USA 107, 5587–5592 (2010).

    CAS  PubMed  Google Scholar 

  93. 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).

    PubMed  PubMed Central  Google Scholar 

  94. Friedrich, R. et al. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 425, 535–539 (2003). This paper describes the molecular mechanism for staphylothrombin formation and activity.

    CAS  PubMed  Google Scholar 

  95. Panizzi, P. et al. Fibrinogen substrate recognition by staphylocoagulase (pro)thrombin complexes. J. Biol. Chem. 281, 1179–1187 (2006).

    CAS  PubMed  Google Scholar 

  96. McAdow, M. et al. Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog. 7, e1002307 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Cheng, A. G. et al. Contribution of coagulases towards Staphylococcus aureus disease and protective immunity. PLoS Pathog. 6, e1001036 (2010). This paper reports that Coa and vWbp are key virulence factors for S. aureus abscess pathogenesis.

    PubMed  PubMed Central  Google Scholar 

  98. McAdow, M. et al. Coagulases as determinants of protective immune responses against Staphylococcus aureus. Infect. Immun. 80, 3389–3398 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Guggenberger, C., Wolz, C., Morrissey, J. A. & Heesemann, J. Two distinct coagulase-dependent barriers protect Staphylococcus aureus from neutrophils in a three dimensional in vitro infection model. PLoS Pathog. 8, e1002434 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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).

    PubMed  PubMed Central  Google Scholar 

  101. Thomer, L. et al. N-acetylglucosaminylation of serine-aspartate repeat proteins promotes Staphylococcus aureus blood stream infection. J. Biol. Chem. 289, 3478–3486 (2014).

    CAS  PubMed  Google Scholar 

  102. Foster, T. J., Geoghegan, J. A., Ganesh, V. K. & Höök, M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat. Rev. Microbiol. 12, 49–62 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 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).

    PubMed  PubMed Central  Google Scholar 

  104. Heilmann, C. et al. Staphylococcus aureus fibronectin-binding protein (FnBP)-mediated adherence to platelets, and aggregation of platelets induced by FnBPA but not by FnBPB. J. Infect. Dis. 190, 321–329 (2004).

    CAS  PubMed  Google Scholar 

  105. Fitzgerald, J. R. et al. Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcγRIIa receptor. Mol. Microbiol. 59, 212–230 (2006).

    CAS  PubMed  Google Scholar 

  106. 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).

    PubMed  PubMed Central  Google Scholar 

  107. Panther, E. et al. Expression and function of adenosine receptors in human dendritic cells. FASEB J. 15, 1963–1970 (2001).

    CAS  PubMed  Google Scholar 

  108. Csóka, B. et al. A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood 110, 2685–2695 (2007).

    PubMed  PubMed Central  Google Scholar 

  109. 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). The paper describes staphylococcal adenosine synthesis as an immune-evasion mechanism.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Berends, E. T. et al. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J. Innate Immun. 2, 576–586 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Thammavongsa, V., Missiakas, D. M. & Schneewind, O. Staphylococcus aureus conversion of neutrophil extracellular traps into deoxyadenosine promotes immune cell death. Science 342, 863–866 (2013). This manuscript reports that S. aureus nuclease and AdsA degrade neutrophil NETs to produce deoxyadenosine and kill macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Forsgren, A. & Nordström, K. Protein A from Staphylococcus aureus: the biological significance of its interaction with IgG. Ann. NY Acad. Sci. 236, 252–266 (1974).

    CAS  PubMed  Google Scholar 

  113. Becker, S., Frankel, M. B., Schneewind, O. & Missiakas, D. M. Release of protein A from the cell wall envelope of Staphylococcus aureus. Proc. Natl Acad. Sci. USA 111, 1574–1579 (2014).

    CAS  PubMed  Google Scholar 

  114. Votintseva, A. A. et al. Prevalence of Staphylococcus aureus protein A (spa) mutants in the community and hospitals in Oxfordshire. BMC Microbiol. 14, 63 (2014).

    PubMed  PubMed Central  Google Scholar 

  115. Shopsin, B. et al. Evaluation of protein A gene polymorphic region DNA sequencing for typing of Staphylococcus aureus strains. J. Clin. Microbiol. 37, 3556–3563 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Forsgren, A. & Sjöquist, J. Protein A from S. aureus. I. Pseudo-immune reaction with human γ-globulin. J. Immunol. 97, 822–827 (1966).

    CAS  PubMed  Google Scholar 

  117. Sasso, E. H., Silverman, G. J. & Mannik, M. Human IgM molecules that bind staphylococcal protein A contain VHIII H chains. J. Immunol. 142, 2778–2783 (1989).

    CAS  PubMed  Google Scholar 

  118. Forsgren, A. & Quie, P. G. Effects of staphylococcal protein A on heat labile opsonins. J. Immunol. 112, 1177–1180 (1974).

    CAS  PubMed  Google Scholar 

  119. Goodyear, C. S. & Silverman, G. J. Death by a B cell superantigen: in vivo VH-targeted apoptotic supraclonal B cell deletion by a staphylococcal toxin. J. Exp. Med. 197, 1125–1139 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Falugi, F., Kim, H. K., Missiakas, D. M. & Schneewind, O. The role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus. mBio 4, e00575–00513 (2013).

    PubMed  PubMed Central  Google Scholar 

  121. Pauli, N. T. et al. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J. Exp. Med. 211, 2331–2339 (2014). The paper describes the expansion of V H 3 clonal plasmablast populations in humans with S. aureus infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Goodyear, C. S. & Silverman, G. J. Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes. Proc. Natl Acad. Sci. USA 101, 11392–11397 (2004).

    CAS  PubMed  Google Scholar 

  123. Kim, H. K., Cheng, A. G., Kim, H.-Y., Missiakas, D. M. & Schneewind, O. Non-toxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections. J. Exp. Med. 207, 1863–1870 (2010). The manuscript describes a vaccine that blocks activity of SpA, a B cell superantigen, to elicit protective immune responses during staphylococcal infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Jardetzky, T. S. et al. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature 368, 711–718 (1994).

    CAS  PubMed  Google Scholar 

  125. Fraser, J. D. & Proft, T. The bacterial superantigen and superantigen-like proteins. Immunol. Rev. 225, 226–243 (2008).

    CAS  PubMed  Google Scholar 

  126. Stach, C. S., Herrera, A. & Schlievert, P. M. Staphylococcal superantigens interact with multiple host receptors to cause serious diseases. Immunol. Res. 59, 177–181 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. Choi, Y. et al. Selective expansion of T cells expressing V β 2 in toxic shock syndrome. J. Exp. Med. 172, 981–984 (1990).

    CAS  PubMed  Google Scholar 

  128. Ferry, T. et al. Analysis of superantigenic toxin Vβ T-cell signatures produced during cases of staphylococcal toxic shock syndrome and septic shock. Clin. Microbiol. Infect. 14, 546–554 (2008).

    CAS  PubMed  Google Scholar 

  129. MacDonald, H. R., Lees, R. K., Baschieri, S., Herrmann, T. & Lussow, A. R. Peripheral T-cell reactivity to bacterial superantigens in vivo: the response/anergy paradox. Immunol. Rev. 133, 105–117 (1993).

    CAS  PubMed  Google Scholar 

  130. Ziegler, C. et al. The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy. EMBO Mol. Med. 3, 652–666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Collins, J., Buckling, A. & Massey, R. C. Identification of factors contributing to T-cell toxicity of Staphylococcus aureus clinical isolates. J. Clin. Microbiol. 46, 2112–2114 (2008).

    PubMed  PubMed Central  Google Scholar 

  132. Nakamura, Y. et al. Staphylococcus δ-toxin promotes allergic skin disease by inducing mass cell degranulation. Nature 503, 397–401 (2013). This paper discovers S. aureus δ-toxin as an agent of mast cell degranulation and atopic disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Novick, R. P. & Geisinger, E. Quorum sensing in staphylococci. Annu. Rev. Genet. 42, 541–564 (2008).

    CAS  PubMed  Google Scholar 

  134. Rogers, D. E. & Melly, M. A. Speculation on the immunology of staphylococcal infections. Ann. NY Acad. Sci. 128, 274–284 (1965).

    CAS  PubMed  Google Scholar 

  135. Holtfreter, S. et al. Antibody responses in furunculosis patients vaccinated with autologous formalin-killed Staphylococcus aureus. Eur. J. Clin. Microbiol. Infect. Dis. 30, 707–717 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Weisman, L. E. et al. A randomized study of a monoclonal antibody (pagibaximab) to prevent staphylococcal sepsis. Pediatrics 128, 271–279 (2011).

    PubMed  Google Scholar 

  137. 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).

    CAS  PubMed  Google Scholar 

  138. Shinefield, H. et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N. Engl. J. Med. 346, 491–496 (2002).

    PubMed  Google Scholar 

  139. Lancefield, R. Current knowledge of type-specific M antigens of group A streptococci. J. Immunol. 89, 307–313 (1962).

    CAS  PubMed  Google Scholar 

  140. Lussow, A. R. & MacDonald, H. R. Differential effects of superantigen-induced “anergy” on priming and effector stages of a T cell-dependent antibody response. Eur. J. Immunol. 24, 445–449 (1994). This report identifies antibodies with broad neutralizing activity for S. aureus β-PFTs.

    CAS  PubMed  Google Scholar 

  141. Rouha, H. et al. Five birds, one stone: neutralization of α-hemolysin and four bi-component leukocidins of Staphylococcus aureus with a single human monoclonal antibody. mAbs 7, 243–254 (2015).

    CAS  PubMed  Google Scholar 

  142. Fitzgerald, J. R. Livestock-associated Staphylococcus aureus: origin, evolution and public health threat. Trends Microbiol. 20, 192–198 (2012).

    CAS  PubMed  Google Scholar 

  143. Lindsay, J. A. Staphylococcus aureus genomics and the impact of horizontal gene transfer. Int. J. Med. Microbiol. 304, 103–109 (2013).

    PubMed  Google Scholar 

  144. Holt, D. C. et al. A very early-branching Staphylococcus aureus lineage lacking the carotenoid pigment staphyloxanthin. Genome Biol. Evol. 3, 881–895 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Baker, H. M. et al. Crystal structures of the staphylococcal toxin SSL5 in complex with sialyl Lewis X reveal a conserved binding site that shares common features with viral and bacterial sialic acid binding proteins. J. Mol. Biol. 374, 1298–1308 (2007).

    CAS  PubMed  Google Scholar 

  146. Geisbrecht, B. V., Hamaoka, B. Y., Perman, B., Zemla, A. & Leahy, D. J. The crystal structures of EAP domains from Staphylococcus aureus reveal an unexpected homology to bacterial superantigens. J. Biol. Chem. 280, 17243–17250 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work on staphylococcal immune evasion was supported by grants from the US National Institute of Allergy and Infectious Diseases AI038897 (O.S.), AI052747 (O.S.) and AI110937 (D.M.). V.T. acknowledges support from the American Heart Association (PST4590023). We apologize to authors whose work was either not referenced or discussed owing to space constraints.

Author information

Authors and Affiliations

  1. Department of Microbiology, University of Chicago, 920 East 58th Street, Chicago, 60637, Illinois, USA

    Vilasack Thammavongsa, Hwan Keun Kim, Dominique Missiakas & Olaf Schneewind

  2. Regeneron Pharmaceuticals, 755 Old Saw Mill River Road, Tarrytown, 10591, New York, USA

    Vilasack Thammavongsa

Authors
  1. Vilasack Thammavongsa
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hwan Keun Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Dominique Missiakas
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Olaf Schneewind
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Olaf Schneewind.

Ethics declarations

Competing interests

The authors declare a conflict of interest as inventors of patents under licence for commercial development of Staphylococcus aureus vaccines.

PowerPoint slides

Glossary

Abscesses

The pathological product of Staphylococcus aureus infection: the harbouring of a staphylococcal abscess community within a pseudocapsule of fibrin deposits that is surrounded by layers of infiltrating immune cells destroying physiological organ tissue.

Recurrence

The propensity of S. aureus infections to reoccur when surgery and/or antibiotic therapy are initially effective.

Superantigen

Molecules that crosslink B cell receptors (that is, IgM) or T cell receptors and major histocompatibility complexes to trigger lymphocyte proliferation, thereby diverting adaptive immune responses.

Anaphylatoxin

Protein fragments generated during complement activation of C3a and C5a that trigger immune responses via C3a and C5a receptors on immune cells.

Enterotoxin

A staphylococcal superantigen that crosslinks major histocompatibility complex class II molecules and T cell receptors, thereby triggering T cell proliferation, anergy and cytokine storms.

Opsonization

Deposition of complement components on bacterial surfaces to promote recognition, phagocytosis and killing by host phagocytes.

Fibrinogen

An abundant glycoprotein of vertebrates that, when cleaved by thrombin or staphylothombin, self-assembles into fibrin clots.

FcαRI

The IgA Fc receptor, which regulates mucosal immune responses in humans.

Fcγ domain

The portion of antibodies dedicated to C1q complement and Fc-receptor activation.

Core genome

The portion of the genome shared by all members of a bacterial species.

Leukocidins

Bacterial secreted toxins targeting white blood cells (leukocytes) for destruction.

Dabigatran

A small molecule that directly binds and inhibits thrombin as well as staphylothrombin, the complex formed between coagulase or von Willebrand Factor-binding protein and prothrombin.

Sortase

The bacterial transpeptidase responsible for anchoring surface proteins to the cell wall envelope.

Fibronectin

A high molecular weight glycoprotein of the extracellular matrix of vertebrates that associates with integrins on cell surfaces.

Factor Xa

The activated serine protease that cleaves prothrombin to activate the clotting cascade of vertebrates; also known as thrombokinase.

Fab domains

The portions of antibodies dedicated to antigen binding.

VH3 clan IgM

IgM derived from one of three clans of variable heavy chain (VH) genes, the products of which provide the scaffold for the antigen-binding determinants of antibodies.

Plasmablasts

Immature B cells in the blood that secrete antibodies.

Autologous vaccine

A whole-cell killed S. aureus vaccine administered to an infected individual that was derived from the patients isolate.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thammavongsa, V., Kim, H., Missiakas, D. et al. Staphylococcal manipulation of host immune responses. Nat Rev Microbiol 13, 529–543 (2015). https://doi.org/10.1038/nrmicro3521

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro3521

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology