Immunologic Research

, Volume 59, Issue 1–3, pp 182–187 | Cite as

Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression

  • Katarina Kulhankova
  • Jessica King
  • Wilmara Salgado-PabónEmail author


Infectious diseases caused by Staphylococcus aureus present a significant clinical and public health problem. S. aureus causes some of the most severe hospital-associated and community-acquired illnesses. Specifically, it is the leading cause of infective endocarditis and osteomyelitis, and the second leading cause of sepsis in the USA. While pathogenesis of S. aureus infections is at the center of current research, many questions remain about the mechanisms underlying staphylococcal toxic shock syndrome (TSS) and associated adaptive immune suppression. Both conditions are mediated by staphylococcal superantigens (SAgs)—secreted staphylococcal toxins that are major S. aureus virulence factors. Toxic shock syndrome toxin-1 (TSST-1) is the SAg responsible for almost all menstrual TSS cases in the USA. TSST-1, staphylococcal enterotoxin B and C are also responsible for most cases of non-menstrual TSS. While SAgs mediate all of the hallmark features of TSS, such as fever, rash, hypotension, and multi-organ dysfunction, they are also capable of enhancing the toxic effects of endogenous endotoxin. This interaction appears to be critical in mediating the severity of TSS and related mortality. In addition, interaction between SAgs and the host immune system has been recognized to result in a unique form of adaptive immune suppression, contributing to poor outcomes of S. aureus infections. Utilizing rabbit models of S. aureus infective endocarditis, pneumonia and sepsis, and molecular genetics techniques, we aim to elucidate the mechanisms of SAg and endotoxin synergism in the pathogenesis of TSS, and examine the cellular and molecular mechanisms underlying SAg-mediated immune dysfunction.


Staphylococcal toxic shock syndrome Superantigens TSST-1 Staphylococcus aureus 


Conflict of interest

None of the authors have conflicts of interest to declare.


  1. 1.
    Klein E, et al. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999–2005. Emerg Infect Dis. 2007;13:1840–6.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Murdoch DR, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169:463–73.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Fowler VG Jr, et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005;293:3012–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Bor DH, et al. Infective endocarditis in the US, 1998–2009: a nationwide study. PLoS ONE. 2013;8:e60033.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Shorr AF, et al. Healthcare-associated bloodstream infection: a distinct entity? Insights from a large US database. Crit Care Med. 2006;34:2588–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Wisplinghoff H, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Spaulding AR, et al. Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev. 2013;26:422–47.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Korol E, et al. A systematic review of risk factors associated with surgical site infections among surgical patients. PLoS ONE. 2013;8:e83743.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    DeVries AS, et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics. PLoS ONE. 2011;6:e22997.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Bergdoll MS. Monkey feeding test for staphylococcal enterotoxin. Methods Enzymol. 1988;165:324–33.CrossRefPubMedGoogle Scholar
  11. 11.
    Giantonio BJ, et al. Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer. J Clin Oncol. 1997;15:1994–2007.PubMedGoogle Scholar
  12. 12.
    Spaulding AR, et al. Vaccination against Staphylococcus aureus pneumonia. J Infect Dis. 2013. doi: 10.1093/infdis/jit823.
  13. 13.
    Schlievert PM. Cytolysins, superantigens, and pneumonia due to community-associated methicillin-resistant Staphylococcus aureus. J Infect Dis. 2009;200:676–8.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Schlievert PM, et al. Staphylococcus aureus exotoxins are present in vivo in tampons. Clin Vaccine Immunol. 2010;17:722–7.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Jaglic Z, et al. Experimental study of pathogenicity of Pasteurella multocida serogroup F in rabbits. Vet Microbiol. 2008;126:168–77.CrossRefPubMedGoogle Scholar
  16. 16.
    Leimbach A, et al. Escherichia coli as an all-rounder: the thin line between commensalism and pathogenicity. Curr Top Microbiol Immunol. 2013;358:3–32.PubMedGoogle Scholar
  17. 17.
    Schlievert PM, et al. Glycerol monolaurate does not alter rhesus macaque (Macaca mulatta) vaginal lactobacilli and is safe for chronic use. Antimicrob Agents Chemother. 2008;52:4448–54.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    CDC (2011) Toxic shock syndrome (other than Streptococcal) (TSS).Google Scholar
  19. 19.
    Gaventa S, et al. Active surveillance for toxic shock syndrome in the United States, 1986. Rev Infect Dis. 1989;11(Suppl 1):S28–34.CrossRefPubMedGoogle Scholar
  20. 20.
    Jain A, Daum RS. Staphylococcal infections in children: Part 3. Pediatr Rev. 1999;20:261–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Jain A, et al. Staphylococcal infections in children: Part 2. Pediatr Rev. 1999;20:219–27.CrossRefPubMedGoogle Scholar
  22. 22.
    Jain A, Daum RS. Staphylococcal infections in children: Part 1. Pediatr Rev. 1999;20:183–91.CrossRefPubMedGoogle Scholar
  23. 23.
    Davis JP, et al. Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med. 1980;303:1429–35.CrossRefPubMedGoogle Scholar
  24. 24.
    Schlievert PM. Staphylococcal enterotoxin B and toxic-shock syndrome toxin-1 are significantly associated with non-menstrual TSS. Lancet. 1986;1:1149–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Schlievert PM, et al. Purification and physicochemical and biological characterization of a staphylococcal pyrogenic exotoxin. Infect Immun. 1979;23:609–17.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Schlievert PM, et al. Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic-shock syndrome. J Infect Dis. 1981;143:509–16.CrossRefPubMedGoogle Scholar
  27. 27.
    Stich N, et al. Staphylococcal superantigen (TSST-1) mutant analysis reveals that t cell activation is required for biological effects in the rabbit including the cytokine storm. Toxins (Basel). 2010;2:2272–88.CrossRefGoogle Scholar
  28. 28.
    Gorbach SL. Microbiology of the gastrointestinal tract. In: Baron S, editor. Medical microbiology. Chap. 95, 4th ed. Galveston, TX: University of Texas Medical Branch at Galveston; 1996.Google Scholar
  29. 29.
    Varga M Textbook of Rabbit Medicine. Butterworth-Heinemann, Elsevier Health Sciences.Google Scholar
  30. 30.
    Sugiyama H, et al. Enhancement of bacterial endotoxin lethality by staphylococcal enterotoxin. J Infect Dis. 1964;114:111–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Schlievert PM, Watson DW. Biogenic amine involvement in pyrogenicity and enhancement of lethal endotoxin shock by group A streptococcal pyrogenic exotoxin. Proc Soc Exp Biol Med. 1979;162:269–74.CrossRefPubMedGoogle Scholar
  32. 32.
    Schlievert PM. Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C. Infect Immun. 1982;36:123–8.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Duranthon V, et al. On the emerging role of rabbit as human disease model and the instrumental role of novel transgenic tools. Transgenic Res. 2012;21:699–713.CrossRefPubMedGoogle Scholar
  34. 34.
    Peng X. Transgenic rabbit models for studying human cardiovascular diseases. Comp Med. 2012;62:472–9.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Lee PK, et al. Fluid replacement protection of rabbits challenged subcutaneous with toxic shock syndrome toxins. Infect Immun. 1991;59:879–84.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Kim YB, Watson DW. A purified group A streptococcal pyrogenic exotoxin. Physiochemical and biological properties including the enhancement of susceptibility to endotoxin lethal shock. J Exp Med. 1970;131:611–22.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Priest BP, et al. Treatment of toxic shock syndrome with endotoxin-neutralizing antibody. J Surg Res. 1989;46:527–31.CrossRefPubMedGoogle Scholar
  38. 38.
    Dinges MM, Schlievert PM. Comparative analysis of lipopolysaccharide-induced tumor necrosis factor alpha activity in serum and lethality in mice and rabbits pretreated with the staphylococcal superantigen toxic shock syndrome toxin 1. Infect Immun. 2001;69:7169–72.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Nolan JP. The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology. 2010;52:1829–35.CrossRefPubMedGoogle Scholar
  40. 40.
    Schlievert PM, et al. Inhibition of ribonucleic acid synthesis by group A streptococcal pyrogenic exotoxin. Infect Immun. 1980;27:542–8.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Canonico PG, Van Zwieten MJ. Swelling of mitochondria from rabbit liver induced by staphylococcal enterotoxin B. J Infect Dis. 1971;124:372–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Stone RL, Schlievert PM. Evidence for the involvement of endotoxin in toxic shock syndrome. J Infect Dis. 1987;155:682–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Chu MC, et al. Growth of toxic shock syndrome toxin 1-producing, tryptophan-requiring strains of Staphylococcus aureus associated with the presence of Escherichia coli. Rev Infect Dis. 1989;11(Suppl 1):S101–3.CrossRefPubMedGoogle Scholar
  44. 44.
    Chow AW, et al. Vaginal colonization with Staphylococcus aureus, positive for toxic-shock marker protein, and Escherichia coli in healthy women. J Infect Dis. 1984;150:80–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Rossi RJ, et al. Staphylococcal enterotoxins condition cells of the innate immune system for Toll-like receptor 4 stimulation. Int Immunol. 2004;16:1751–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Wheeler MD. Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res Health. 2003;27:300–6.PubMedGoogle Scholar
  47. 47.
    Fast DJ, et al. Toxic shock syndrome-associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumor necrosis factor production. Infect Immun. 1989;57:291–4.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Luhm J, et al. One-way synergistic effect of low superantigen concentrations on lipopolysaccharide-induced cytokine production. J Interferon Cytokine Res. 1997;17:229–38.CrossRefPubMedGoogle Scholar
  49. 49.
    Beezhold DH, et al. Endotoxin enhancement of toxic shock syndrome toxin 1-induced secretion of interleukin 1 by murine macrophages. Rev Infect Dis. 1989;11(Suppl 1):S289–93.CrossRefPubMedGoogle Scholar
  50. 50.
    Beezhold DH, et al. Synergistic induction of interleukin-1 by endotoxin and toxic shock syndrome toxin-1 using rat macrophages. Infect Immun. 1987;55:2865–9.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Chen X, et al. Endotoxin exacerbates immunologically induced liver injury in cooperation with interferon-gamma. Inflamm Res. 2000;49:571–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Keane WF, et al. Enhancement of endotoxin-induced isolated renal tubular cell injury by toxic shock syndrome toxin 1. Am J Pathol. 1986;122:169–76.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Callahan JE, et al. Stimulation of B10.BR T cells with superantigenic staphylococcal toxins. J Immunol. 1990;144:2473–9.PubMedGoogle Scholar
  54. 54.
    Choi Y, et al. Selective expansion of T cells expressing V beta 2 in toxic shock syndrome. J Exp Med. 1990;172:981–4.CrossRefPubMedGoogle Scholar
  55. 55.
    Fraser JD. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989;339:221–3.CrossRefPubMedGoogle Scholar
  56. 56.
    Scholl PR, et al. Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 bind to distinct sites on HLA-DR and HLA-DQ molecules. J Immunol. 1989;143:2583–8.PubMedGoogle Scholar
  57. 57.
    White J, et al. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989;56:27–35.CrossRefPubMedGoogle Scholar
  58. 58.
    Frederick DM, et al. Fatal disseminated herpes simplex virus infection in a previously healthy pregnant woman. A case report. J Reprod Med. 2002;47:591–6.PubMedGoogle Scholar
  59. 59.
    Cockerill FR, et al. Molecular, serological, and clinical features of 16 consecutive cases of invasive streptococcal disease. Southeastern Minnesota streptococcal working group. Clin Infect Dis. 1998;26:1448–58.CrossRefPubMedGoogle Scholar
  60. 60.
    Saha DC, et al. Lipopolysaccharide- and superantigen-modulated superoxide production and monocyte hyporesponsiveness to activating stimuli in sepsis. Shock. 2012;38:43–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Vergeront JM, et al. Prevalence of serum antibody to staphylococcal enterotoxin F among Wisconsin residents: implications for toxic-shock syndrome. J Infect Dis. 1983;148:692–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Poindexter NJ, Schlievert PM. Suppression of immunoglobulin-secreting cells from human peripheral blood by toxic-shock-syndrome toxin-1. J Infect Dis. 1986;153:772–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Spaulding AR, et al. Immunity to Staphylococcus aureus secreted proteins protects rabbits from serious illnesses. Vaccine. 2012;30:5099–109.PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Kansal R, et al. Structural and functional properties of antibodies to the superantigen TSST-1 and their relationship to menstrual toxic shock syndrome. J Clin Immunol. 2007;27:327–38.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Katarina Kulhankova
    • 1
  • Jessica King
    • 1
  • Wilmara Salgado-Pabón
    • 1
    Email author
  1. 1.Department of MicrobiologyUniversity of Iowa Carver College of MedicineIowa CityUSA

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