Abstract
Non-menstrual toxic shock syndrome (non-mTSS) is a life-threatening disease caused by Staphylococcus aureus strains producing superantigens, such as staphylococcal enterotoxins A, B, C, and toxic shock syndrome toxin-1 (TSST-1). However, little is known about why the TSS cases are rare, although S. aureus strains frequently carry a tst gene, which encodes TSST-1. To answer this question, the amount of TSST-1 produced by 541 clinical isolates was measured in both the presence and absence of serum supplementation to growth media. Then a set of S. aureus strains with similar genetic backgrounds isolated from patients presenting with non-mTSS and those with clinical manifestations other than non-mTSS was compared for their TSST-1 inducibility by human serum, and their whole-genome sequences were determined. Subsequently, the association of mutations identified in the tst promoter of non-mTSS strains with TSST-1 inducibility by human serum was evaluated by constructing promoter replacement mutants and green fluorescent protein (GFP) reporter recombinants. Results showed that 39 out of 541 clinical isolates (7.2%), including strains isolated from non-mTSS patients, had enhanced production of TSST-1 in the presence of serum. TSST-1 inducibility by human serum was more clearly seen in non-mTSS strains of clonal complex (CC)-5. Moreover, the whole-genome sequence analysis identified a set of sequence variations at a putative SarA-binding site of the tst promoter. This sequence variation was proven to be partially responsible for the induction of TSST-1 production by human serum. We conclude that the onset of staphylococcal toxic shock syndrome caused by TSST-1-producing CC-5 strains seem at least partially initiated by serum induction of TSST-1, which is regulated by the mutation of putative SarA-binding site at the tst promoter.
Highlights
Staphylococcus aureus causes a wide variety of infectious diseases ranging from mild local infections, such as impetigo, to lifethreatening diseases, including toxic shock syndrome (TSS) (Lowy, 1998)
Thirtynine strains (24.8%) produced toxic shock syndrome toxin-1 (TSST-1) at titers of equal or more than 8, 192, and 88 strains (56.1%) produced TSST-1 at titers less than 32. These results indicated that the TSST1-producing strains could be classified into three groups: (1) strains showing increased production of TSST-1 following supplementation of horse serum, (2) strains producing a similar amount of TSST-1 with or without supplementation of horse serum, and (3) strains showing decreased production of TSST1 following supplementation of horse serum
Six methicillin-resistant S. aureus (MRSA) strains isolated from fatal TSS cases, including Sak-1 strain, belonged to the first group, suggesting that there might be an association between TSST-1 induction by serum and development of TSS
Summary
Staphylococcus aureus causes a wide variety of infectious diseases ranging from mild local infections, such as impetigo, to lifethreatening diseases, including toxic shock syndrome (TSS) (Lowy, 1998). According to the active surveillance of TSS reported by DeVries et al (2011) the prevalence of TSS peaked at 13.7 per 100,000 in 1980, but has rapidly decreased to approximately 1.5–2.5 and 0.52 in 1986 and 2000–2003, respectively. The rate of non-mTSS among all TSS cases increased from 9% in 1979–1980 (Hajjeh et al, 1999) to 46% in 2000–2006 (DeVries et al, 2011). Even though the mortality rate of mTSS decreased gradually from 5.5% in 1979–1980 to 1.8% in 1987–1996 (Jenul and Horswill, 2019) and eventually to 0% in 2000–2006 (DeVries et al, 2011), that of non-mTSS remained high (8.5, 6, and 4%, respectively, for the three periods of time mentioned above). The difficulty in prevention and high mortality of non-mTSS render it one of the most problematic infectious diseases caused by S. aureus
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