Medical Microbiology and Immunology

, Volume 207, Issue 5–6, pp 297–306 | Cite as

Contribution of toxic shock syndrome toxin-1 to systemic inflammation investigated by a mouse model of cervicovaginal infection with Staphylococcus aureus

  • Krisana AsanoEmail author
  • Kouji Narita
  • Shouhei Hirose
  • Akio Nakane
Original Investigation


Toxic shock syndrome toxin-1 (TSST-1), a superantigen produced by Staphylococcus aureus is a causative agent of toxic shock syndrome (TSS) that is frequently associated with tampon use. It has long been suggested that TSS is induced when TSST-1 circulates through the body. However, the systemic distribution of TSST-1 from vagina or uterus has never been demonstrated. In this study, a mouse cervicovaginal infection model was established. Transcervical inoculation with a virulence strain of S. aureus and its derivative TSST-1-deficient mutant demonstrated that TSST-1 distributed to the bloodstream and spleen, and promoted systemic inflammation without bacteremia. Transcervical administration with the wild-type toxin and a superantigen-deficient mutant of TSST-1 (mTSST-1) demonstrated that the superantigenic activity of TSST-1 was essential to stimulate the systemic inflammation. Furthermore, this activity was not promoted by co-transcervical inoculation with lipopolysaccharides. The circulating TSST-1 and systemic inflammation rapidly reduced at 48 h after administration, suggesting that persistence of S. aureus in the uterus may be involved in long-term complications of TSS. Transcervical inoculation with mTSST-1-producing S. aureus showed that this toxin promoted bacterial number, uterine tissue damage, and localization of bacterial cells around uterine cavity. The results suggest that TSST-1 enhances S. aureus burden in uterine cavity, the secreted TSST-1 distributes into circulation system, and then systemic inflammation is induced.


Staphylococcus aureus Tampon-related toxic shock syndrome Toxic shock syndrome toxin-1 Cervicovaginal infection 



We would like to thank Prof. Trinad Chakraborty from Institute of Medical Microbiology, University Teaching Hospital of Giessen, Germany, and Dr. Jens Bo Andersen from Department. of Microbiology and Risk Assessment, National Food Institute, DTU, Technical University of Denmark, for kindly providing a thermosensitive shuttle vector, pAULA and a YFP-expressing plasmid, pJEBAN3, respectively. This study was supported by the Japan Society for the Promotion of Science [Grant numbers 26460517 and 17K08819 (KS) and 16H5185 (AN)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

430_2018_551_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 19 KB)
430_2018_551_MOESM2_ESM.pdf (354 kb)
Supplementary material 2 (PDF 353 KB)


  1. 1.
    Lowy FD (1998) Staphylococcus aureus infections. N Engl J Med 339:520–532. CrossRefGoogle Scholar
  2. 2.
    Dinges MM, Orwin PM, Schlievert PM (2000) Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 13:16–34. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stach CS, Herrera A, Schlievert PM (2014) Staphylococcal superantigens interact with multiple host receptors to cause serious diseases. Immunol Res 59:177–181. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Josse J, Laurent F, Diot A (2017) Staphylococcal adhesion and host cell invasion: fibronectin-binding and other mechanisms. Front Microbiol 8:2433. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lowy FD (2003) Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest 111:1265–1273. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Matouskova I, Janout V (2008) Current knowledge of methicillin-resistant Staphylococcus aureus and community-associated methicillin-resistant Staphylococcus aureus. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 152:191–202. CrossRefPubMedGoogle Scholar
  7. 7.
    Kubica M, Guzik K, Koziel J et al (2008) A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages. PLoS One 3:e1409. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Strobel M, Pförtner H, Tuchscherr L et al (2016) Post-invasion events after infection with Staphylococcus aureus are strongly dependent on both the host cell type and the infecting S. aureus strain. Clin Microbiol Infect 22:799–809. CrossRefPubMedGoogle Scholar
  9. 9.
    Gresham HD, Lowrance JH, Caver TE, Wilson BS, Cheung AL, Lindberg FP (2000) Survival of Staphylococcus aureus inside neutrophils contributes to infection. J Immunol 164:3713–3722. CrossRefPubMedGoogle Scholar
  10. 10.
    Horn J, Stelzner K, Rude T, Fraunholz M (2017) Inside job: Staphylococcus aureus host-pathogen interactions. Int J Med Microbiol. CrossRefPubMedGoogle Scholar
  11. 11.
    Chesney PJ (1989) Clinical aspects and spectrum of illness of toxic shock syndrome: overview. Rev Infect Dis 11:S1–S7. CrossRefPubMedGoogle Scholar
  12. 12.
    Kulhankova K, King J, Salgado-Pabón W (2014) Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression. Immunol Res 59:182–187. CrossRefPubMedGoogle Scholar
  13. 13.
    Shands KN, Schmid GP, Dan BB et al (1980) Toxic-shock syndrome in menstruating women: its association with tampon use and Staphylococcus aureus and the clinical features in 52 cases. N Engl J Med 303:1436–1442. CrossRefPubMedGoogle Scholar
  14. 14.
    Asano K, Asano Y, Ono HK, Nakane A (2014) Suppression of starvation-induced autophagy by recombinant toxic shock syndrome toxin-1 in epithelial cells. PLoS One 9:e113018. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nakane A, Okamoto M, Asano M, Kohanawa M, Minagawa T (1995) Endogenous gamma interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice. Infect Immun 63:1165–1172PubMedPubMedCentralGoogle Scholar
  16. 16.
    Nair D, Memmi G, Hernandez D et al (2011) Whole-genome sequencing of Staphylococcus aureus strain RN4220, a key laboratory strain used in virulence research, identifies mutations that affect not only virulence factors but also the fitness of the strain. J Bacteriol 193:2332–2335. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bonventre PF, Heeg H, Edwards CK III, Cullen CM (1995) A mutation at histidine residue 135 of toxic shock syndrome toxin (TSST-1) yields an immunogenic protein with minimal toxicity. Infect Immun 63:509–515PubMedPubMedCentralGoogle Scholar
  18. 18.
    Hu DL, Omoe K, Sasaki S et al (2003) Vaccination with nontoxic mutant toxic shock syndrome toxin 1 protects against Staphylococcus aureus infection. J Infect Dis 188:743–752. CrossRefPubMedGoogle Scholar
  19. 19.
    Brown RC, Hopps HC (1973) Staining of bacteria in tissue sections: a reliable gram stain method. Am J Clin Pathol 60:234–240. CrossRefPubMedGoogle Scholar
  20. 20.
    Reingold AL, Hargrett NT, Dan BB, Shands KN, Strickland BY, Broome CV (1982) Nonmenstrual toxic shock syndrome: a review of 130 cases. Ann Intern Med 96:871–874. CrossRefPubMedGoogle Scholar
  21. 21.
    O’Hanlon DE, Moench TR, Cone RA (2011) In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis 11:200. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Davis JP, Chesney PJ, Wan PJ, LaVenture M (1980) Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med 303:1429–1435. CrossRefPubMedGoogle Scholar
  23. 23.
    De Boer ML, Kum WW, Pang LT, Chow AW (1999) Co-production of staphylococcal enterotoxin A with toxic shock syndrome toxin-1 (TSST-1) enhances TSST-1 mediated mortality in a d-galactosamine sensitized mouse model of lethal shock. Microb Pathog 27:61–70. CrossRefPubMedGoogle Scholar
  24. 24.
    Andersen JB, Roldgaard BB, Lindner AB, Christensen BB, Licht TR (2006) Construction of a multiple fluorescence labelling system for use in co-invasion studies of Listeria monocytogenes. BMC Microbiol 6:86. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
  2. 2.Department of Biopolymer and Health ScienceHirosaki University Graduate School of MedicineHirosakiJapan
  3. 3.Institute for Animal Experimentation, Hirosaki University Graduate School of MedicineHirosakiJapan

Personalised recommendations