Toxic Shock Syndrome Toxin 1 Evaluation and Antibiotic Impact in a Transgenic Model of Staphylococcal Soft Tissue Infection

Abstract

Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 Staphylococcus aureus, is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an S. aureus abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection in vivo. HLA-DQ8 mice were infected subcutaneously with a tst-positive CC30 methicillin-sensitive S. aureus clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vβ subsets 3 and 13 in vitro and instigated cytokine release in vivo, confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 μg/ml) and draining lymph nodes (0 to 0.2 μg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression. IMPORTANCE Staphylococcal toxic shock syndrome (TSS) is a life-threatening illness causing fever, rash, and shock, attributed to toxins produced by the bacterium Staphylococcus aureus, mainly toxic shock syndrome toxin 1 (TSST-1). TSS was in the past commonly linked with menstruation and high-absorbency tampons; now, TSS is more frequently triggered by other staphylococcal infections, particularly of skin and soft tissue. Investigating the progress and treatment of TSS in patients is challenging, as TSS is rare; animal models do not mimic TSS adequately, as toxins interact best with human immune cells. We developed a new model of staphylococcal soft tissue infection in mice producing human immune cell proteins, rendering them TSST-1 sensitive, to investigate TSS. The significance of our research was that TSST-1 was found in soft tissues and immune organs of mice and that early treatment of mice with the antibiotic clindamycin altered TSST-1 production. Therefore, the early treatment of patients suspected of having TSS with clindamycin may influence their response to treatment.

Dysbiosis From a Microbial and Host Perspective Relative to Oral Health and Disease

“…This elegant but simple experiment demonstrated the potent effect of antibiotics on a change in the homeostatic balance in natural biofilm formation on tooth surfaces. In clinical settings it has become apparent that a better understanding of antibiotics is imperative in the balance between health and disease (Sharma et al, 2019). Antibiotic sensitivity and resistance have to be taken into consideration FIGURE 2 | Illustration of experiment showing how an overhanging dental restoration can influence homeostatic balance by influences on tissue integrity, inflammatory responsiveness etc.…”

“…In clinical settings it has become apparent that a better understanding of antibiotics is imperative in the balance between health and disease (Sharma et al, 2019 ). Antibiotic sensitivity and resistance have to be taken into consideration (Marcinkiewicz et al, 2013 ).…”

Occurrence and enterotoxin gene profiles of Staphylococcus aureus isolated from retail chicken meat

“…The ability of these organisms to cause food borne illness is mainly attributed to the production of variety of heat stable enterotoxins, which are encoded by enterotoxin genes carried either in prophage or plasmids (Schelin et al., 2011). The occurrence of genes encoding both classical as well as new types of staphylococcal enterotoxin in retail meat and meat products have been well documented by researchers worldwide (Fisher et al., 2018; Rahimi et al., 2013; Sahin et al., 2020; Sharma et al., 2019).…”

Population Analysis of Staphylococcus aureus Reveals a Cryptic, Highly Prevalent Superantigen SElW That Contributes to the Pathogenesis of Bacteremia

“…Together, these data indicate that sufficient expression levels of SElW in vivo promote the pathogenicity of S. aureus . While splenocytes from HLA-transgenic mice are more sensitive to SAg activity than their C57BL/6 progenitors, they are not as responsive as human PBMCs ( 39 ). Added to this evidence, murine vasculature is not very representative of the human system and the vascular leakage reported in rabbit TSS models may not be as pronounced in mice.…”