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