S. aureus Toxic Shock Syndrome Toxin-1

Staphylococcus aureus is one of the most common pathogens of hospital-acquired and community-acquired infections, with the highest isolation rate, and is a major problem in clinical anti-infection treatment. The high pathogenicity and rapid spread of Staphylococcus aureus are strongly correlated with the secretion of virulence factors. Its main virulence factors, such as pore-forming toxins, exfoliating toxins, and superantigens, have been proven to be associated with certain diseases. Toxic shock toxin-1 (TSST-1) is an exotoxin produced by phage group I Staphylococcus aureus, belonging to the pyrogenic superantigen (SAG) family, which can cause symptoms such as desquamative rash, high fever, organ dysfunction, and even toxic shock, with a high mortality rate. Therefore, the pathogenic mechanism and clinical significance of TSST-1 have been widely concerned by scholars at home and abroad. 1. Discovery of TSST-1 In 1978, TODD et al. first reported an acute multisystem infection characterized by fever, rash, and hypotensive shock, named toxic shock syndrome (TSS), and proposed that this disease was closely related to Staphylococcus aureus infection, which attracted widespread attention in the medical community. In 1981, researchers isolated pyrogenic exotoxin C (PEC) and enterotoxin (SE) F from TSS-related Staphylococcus aureus, which were closely related to the onset of the disease, and classified them as toxic shock associated protein (TSAP). Subsequently, a large amount of evidence showed that PEC and SEF were highly similar in biochemistry, biology, and immunology. Therefore, at the first international TSS seminar in 1984, they were officially classified as one and renamed TSST-1.

Figure 1. S. aureus superantigens (SAgs) and pore-forming toxins (PFTs). (Sources: Miller LS, et al. 2020)

Expression and Regulation of TSST-1Since the production of TSST-1 is directly related to the disease, studying its expression and regulation will help to provide a basis for the formulation of reasonable infection control strategies for TSST-1 gene-positive Staphylococcus aureus. TSST-1 is encoded by the tst gene, which exists in the Staphylococcus pathogenicity island 1 (sapI1) on the bacterial chromosome. The gene is 207 bp in length and encodes 234 amino acids. The expression of TSST-1 is regulated by multiple environmental and genetic systems. Various factors (including glucose, O₂, magnesium ions, α and β chains of hemoglobin, antimicrobial drugs, pH and bacterial microenvironment) can trigger the regulatory role of virulence regulators in TSST-1 expression. The quorum sensing system (Agr) and the staphylococcal auxiliary regulator (Sar) A family are important virulence regulators of TSST-1. Agr can positively regulate the expression of TSST-1 by producing high levels of effector molecule RNA III, inhibiting the transcription and translation of toxin repressor (Rot). In contrast, the SarA family negatively regulates the expression of TSST-1 by binding to the tst gene promoter and is an effective inhibitor of TSST-1 expression in the strain S. aureus MN8. In addition, regulatory factors such as carbon decomposition protein A (CCPA) gene, staphylococcal respiratory response two-component system (SrrAB), and σB can also play a role under specific conditions and jointly affect the expression of TSST-1. Some studies have also found that SrrAB, RNA III, SarT and CCPA are abnormally expressed only in specific strains, indicating that the regulatory networks of different strains may be different. Methicillin-sensitive Staphylococcus aureus (MSSA) has a greater potential to secrete toxins than methicillin-resistant Staphylococcus aureus (MRSA), which may be related to the lack of staphylococcal chromosome mec gene cassette (SCCCmec) elements in MSSA, resulting in a lower genetic fitness burden in its isolates.

Pathogenic mechanism of TSST-1 TSST-1 can be expressed when the tst gene is activated. TSST-1 is a single polypeptide chain with an isoelectric point of 7.2. It mainly causes local and systemic damage to the body by exerting superantigen characteristics and enhancing susceptibility to endotoxins. The skin and mucous membranes are important barriers for the body to resist pathogen infection. TSST-1 can produce chemokines by binding to CD40 on the surface of vaginal epithelial cells, destroying the mucosal barrier. It is the only known superantigen that can penetrate the mucosal surface and cause vaginal TSS. After entering the body, TSST-1 does not need to be processed and directly binds to the outer side of the antigen binding groove of the major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells without restriction, forming an MHCⅡ-TSST-1 complex, activating the specific β chain V region (TCR-Vβ) of the T cell antigen receptor. T cells activate, proliferate and release a large number of inflammatory cytokines, causing a strong immune response, which ultimately leads to uncontrolled inflammatory response and multi-organ damage. At the same time, TSST-1 can also inhibit B cells from differentiating into immunoglobulin-secreting cells, thereby evading the host's immune attack. In addition, TSST-1 can directly damage Kupffer cells and sinusoidal endothelial cells, inhibit endotoxin degranulation, and cause a large amount of endotoxin to accumulate, thereby entering the systemic blood circulation and causing endotoxemia. High levels of endotoxin in portal vein blood can also directly damage liver cells, thereby affecting the liver's detoxification ability. Only very low levels of endotoxin can cause severe hypotension and shock in patients, and even lead to death. TSST-1 can also bind to endothelial cells to cause capillary leakage, leading to endothelial cell death and increased sensitivity to endotoxins, and enhancing skin allergic reactions.

TSST-1
Toxic shock toxin-1
Staphylococcal enterotoxin F