scholarly journals Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Patrick M. Schlievert ◽  
Michael P. Cahill ◽  
Bruce S. Hostager ◽  
Amanda J. Brosnahan ◽  
Aloysius J. Klingelhutz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Epithelial Cells ◽  
Toxic Shock Syndrome ◽  
Costimulatory Molecule ◽  
Rabbit Model ◽  
Toxic Shock ◽  
Entire Family ◽  
Chemokine Production ◽  
Content Type ◽  
Vaginal Epithelial Cells

ABSTRACTMucosal and skin tissues form barriers to infection by most bacterial pathogens.Staphylococcus aureuscauses diseases across these barriers in part dependent on the proinflammatory properties of superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment.IMPORTANCEMenstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization byStaphylococcus aureusproducing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.

scholarly journals The Innate Immune System Is Activated by Stimulation of Vaginal Epithelial Cells with Staphylococcus aureus and Toxic Shock Syndrome Toxin 1

2005 ◽  
Vol 73 (4) ◽  
pp. 2164-2174 ◽  
Author(s):  
Marnie L. Peterson ◽  
Kevin Ault ◽  
Mary J. Kremer ◽  
Aloysius J. Klingelhutz ◽  
Catherine C. Davis ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune System ◽  
Epithelial Cells ◽  
Innate Immune System ◽  
Toxic Shock Syndrome ◽  
Innate Immune ◽  
Toxic Shock ◽  
Down Regulation ◽  
Vaginal Epithelial Cells ◽  
Stimulation Of

ABSTRACT Despite knowledge of the effects of toxic shock syndrome (TSS) toxin 1 (TSST-1) on the adaptive immune system, little is known about stimulation of the innate immune system, particularly epithelial cells. This study investigated the interactions of TSS Staphylococcus aureus and TSST-1 with human vaginal epithelial cells (HVECs) and porcine mucosal surfaces. When cocultured with HVECs for 6 h, TSS S. aureus MN8 proliferated, formed aggregates on the HVEC surfaces, and produced exotoxins. Receptor binding studies showed that 35S-TSST-1 bound to 5 × 104 receptors per HVEC, with saturation at 15 min. Affymetrix Human GeneChip U133A microarray analysis determined S. aureus MNSM (100 bacteria/HVEC) caused at least twofold up- or down-regulation of 410 HVEC genes by 6 h; these data were also confirmed with S. aureus MN8. TSST-1 (100 μg/ml) caused up- or down-regulation of 2,386 HVEC genes by 6 h. In response to S. aureus, the HVEC genes most up-regulated compared to those in controls were those coding for chemokines or cytokines—MIP-3α, 478-fold; GRO-α, 26-fold; GRO-β, 14-fold; and GRO-γ, 30-fold—suggesting activation of innate immunity. TSST-1 also caused up-regulation of chemokine/cytokine genes. Chemokine/cytokine gene up-regulation was confirmed by enzyme-linked immunosorbent assays measuring the corresponding proteins induced by S. aureus and TSST-1. S. aureus MN8, when incubated with porcine vaginal tissue, increased the flux of 35S-TSST-1 across the mucosal surface. This was accompanied by influx of lymphocytes into the upper layers of the tissue. These data suggest innate immune system activation through epithelial cells, reflected in chemokine/cytokine production and influx of lymphocytes, may cause changes in vaginal mucosa permeability, facilitating TSST-1 penetration.

scholarly journals Interleukin-10 (IL-10) Produced by Mutant Toxic Shock Syndrome Toxin 1 Vaccine-Induced Memory T Cells Downregulates IL-17 Production and Abrogates the Protective Effect against Staphylococcus aureus Infection

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Kouji Narita ◽  
Dong-Liang Hu ◽  
Krisana Asano ◽  
Akio Nakane
Keyword(s):  
Staphylococcus Aureus ◽  
T Cells ◽  
Infectious Diseases ◽  
Protective Effect ◽  
Toxic Shock Syndrome ◽  
Long Term Memory ◽  
Toxic Shock ◽  
Content Type ◽  
Memory Phase ◽  
Toxic Shock Syndrome Toxin

ABSTRACT Development of long-term memory is crucial for vaccine-induced adaptive immunity against infectious diseases such as Staphylococcus aureus infection. Toxic shock syndrome toxin 1 (TSST-1), one of the superantigens produced by S. aureus, is a possible vaccine candidate against infectious diseases caused by this pathogen. We previously reported that vaccination with less toxic mutant TSST-1 (mTSST-1) induced T helper 17 (Th17) cells and elicited interleukin-17A (IL-17A)-mediated protection against S. aureus infection 1 week after vaccination. In the present study, we investigated the host immune response induced by mTSST-1 vaccination in the memory phase, 12 weeks after the final vaccination. The protective effect and IL-17A production after vaccination with mTSST-1 were eliminated because of IL-10 production. In the presence of IL-10-neutralizing monoclonal antibody (mAb), IL-17A production was restored in culture supernatants of CD4+ T cells and macrophages sorted from the spleens of vaccinated mice. Vaccinated mice treated with anti-IL-10 mAb were protected against systemic S. aureus infection in the memory phase. From these results, it was suggested that IL-10 produced in the memory phase suppresses the IL-17A-dependent vaccine effect through downregulation of IL-17A production.

scholarly journals Impact of Currently Marketed Tampons and Menstrual Cups onStaphylococcus aureusGrowth and Toxic Shock Syndrome Toxin 1 ProductionIn Vitro

2018 ◽  
Vol 84 (12) ◽  
pp. e00351-18 ◽  
Author(s):  
Louis Nonfoux ◽  
Myriam Chiaruzzi ◽  
Cédric Badiou ◽  
Jessica Baude ◽  
Anne Tristan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Toxic Shock Syndrome ◽  
Severe Disease ◽  
Toxin Production ◽  
Toxic Shock ◽  
Content Type ◽  
Physiological Conditions ◽  
Simple Protocol ◽  
Toxic Shock Syndrome Toxin ◽  
The Impact

ABSTRACTFifteen currently marketed intravaginal protection products (11 types of tampon and 4 types of menstrual cup) were tested by the modified tampon sac method to determine their effect onStaphylococcus aureusgrowth and toxic shock syndrome toxin 1 (TSST-1) production. Most tampons reducedS. aureusgrowth and TSST-1 production, with differences based on brand and composition, and the level ofS. aureusgrowth was higher in destructured than in unaltered tampons. We observed higher levels ofS. aureusgrowth and toxin production in menstrual cups than in tampons, potentially due to the additional air introduced into the bag by cups, with differences based on cup composition and size.IMPORTANCEMenstrual toxic shock syndrome is a rare but severe disease. It occurs in healthy women vaginally colonized byStaphylococcus aureusproducing toxic shock syndrome toxin 1 using intravaginal protection, such as tampons or menstrual cups. Intravaginal protection induces TSS by the collection of catamenial products, which act as a growth medium forS. aureus. Previous studies evaluated the impact of tampon composition onS. aureusproducing toxic shock syndrome toxin 1, but they are not recent and did not include menstrual cups. This study demonstrates that highly reproducible results forS. aureusgrowth and TSST-1 production can be obtained by using a simple protocol that reproduces the physiological conditions of tampon and cup usage as closely as possible, providing recommendations for tampon or cup use to both manufacturers and consumers. Notably, our results do not show that menstrual cups are safer than tampons and suggest that they require similar precautions.

scholarly journals Staphylococcal TSST-1 Association with Eczema Herpeticum in Humans

mSphere ◽  
2021 ◽  
Author(s):  
Patrick M. Schlievert ◽  
Richard J. Roller ◽  
Samuel H. Kilgore ◽  
Miguel Villarreal ◽  
Aloysius J. Klingelhutz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Atopic Dermatitis ◽  
Toxic Shock Syndrome ◽  
Herpes Simplex Virus Infection ◽  
Severe Form ◽  
Toxic Shock ◽  
Content Type ◽  
Eczema Herpeticum ◽  
Toxic Shock Syndrome Toxin ◽  
Simplex Virus

Atopic dermatitis (eczema, AD) with concurrent herpes simplex virus infection (eczema herpeticum, ADEH) is a severe form of AD. We show that ADEH patients are colonized with Staphylococcus aureus that primarily produces the superantigen toxic shock syndrome toxin-1 (TSST-1); however, significantly but to a lesser extent the superantigens staphylococcal enterotoxins A, B, and C are also represented in ADEH.

scholarly journals Chronic Superantigen Exposure Induces Systemic Inflammation, Elevated Bloodstream Endotoxin, and Abnormal Glucose Tolerance in Rabbits: Possible Role in Diabetes

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Bao G. Vu ◽  
Christopher S. Stach ◽  
Katarina Kulhankova ◽  
Wilmara Salgado-Pabón ◽  
Aloysius J. Klingelhutz ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Staphylococcus Aureus ◽  
Glucose Tolerance ◽  
Systemic Inflammation ◽  
Toxic Shock Syndrome ◽  
Toxic Shock ◽  
Content Type ◽  
Toxic Shock Syndrome Toxin

ABSTRACTExcessive weight and obesity are associated with the development of diabetes mellitus type 2 (DMII) in humans. They also pose high risks ofStaphylococcus aureuscolonization and overt infections.S. aureuscauses a wide range of severe illnesses in both healthy and immunocompromised individuals. AmongS. aureusvirulence factors, superantigens are essential for pathogenicity. In this study, we show that rabbits that are chronically exposed toS. aureussuperantigen toxic shock syndrome toxin-1 (TSST-1) experience impaired glucose tolerance, systemic inflammation, and elevated endotoxin levels in the bloodstream, all of which are common findings in DMII. Additionally, such DMII-associated findings are also seen through effects of TSST-1 on isolated adipocytes. Collectively, our findings suggest that chronic exposure toS. aureussuperantigens facilitates the development of DMII, which may lead to therapeutic targeting ofS. aureusand its superantigens.IMPORTANCEObesity has a strong correlation with type 2 diabetes, in which fatty tissue, containing adipocytes, contributes to the development of the illness through altered metabolism and chronic inflammation. The human microbiome changes in persons with obesity and type 2 diabetes, including increases inStaphylococcus aureuscolonization and overt infections. While the microbiome is essential for human wellness, there is little understanding of the role of microbes in obesity or the development of diabetes. Here, we demonstrate that theS. aureussuperantigen toxic shock syndrome toxin-1 (TSST-1), an essential exotoxin in pathogenesis, induces inflammation, lipolysis, and insulin resistance in adipocytes bothin vitroandin vivo. Chronic stimulation of rabbits with TSST-1 results in impaired systemic glucose tolerance, the hallmark finding in type 2 diabetes in humans, suggesting a role ofS. aureusand its superantigens in the progression to type 2 diabetes.

scholarly journals Staphylococcal Enterotoxin C Subtypes Are Differentially Associated with Human Infections and Immunobiological Activities

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Olivia N. Chuang-Smith ◽  
Patrick M. Schlievert
Keyword(s):  
Virulence Factors ◽  
Toxic Shock Syndrome ◽  
Mononuclear Cells ◽  
Rabbit Model ◽  
Purpura Fulminans ◽  
Staphylococcal Enterotoxin ◽  
Thymidine Uptake ◽  
Toxic Shock ◽  
Content Type ◽  
Hemorrhagic Pneumonia

ABSTRACT Staphylococcus aureus causes significant infections, responsible for toxic shock syndrome (TSS), hemorrhagic pneumonia, and many other infections. S. aureus secretes virulence factors, which include superantigens such as staphylococcal enterotoxins (SEs). We examined differences in immunobiological activities and disease associations among the four human SEC subtypes. We sequenced the sec gene from 35 human isolates to determine SEC subtypes. Upon finding differences in disease association, we used a [3H]thymidine uptake assay to examine SEC-induced superantigenicity. We also employed a rabbit model of SEC-induced TSS. SEC-2 and SEC-3 were associated with menstrual TSS and vaginal isolates from healthy women, whereas SEC-4 was produced by USA400 isolates causing purpura fulminans and hemorrhagic pneumonia. SEC subtypes differed in potency in a TSS rabbit model and in superantigenicity. There was no difference in superantigenicity when tested on human peripheral blood mononuclear cells. Despite differences, all SECs reacted with polyclonal antibodies raised against the other SEC subtypes. The associations of SEC subtypes with different infections suggest that S. aureus produces virulence factors according to host niches. IMPORTANCE Staphylococcal enterotoxin C has four subtypes that cause human diseases, designated SEC-1 to -4. This study shows that SEC-2 and SEC-3 are the most toxic subtypes in a rabbit model and are associated with human vaginal infections or colonization in association with another superantigen, toxic shock syndrome toxin 1. SEC-4 is associated with purpura fulminans and hemorrhagic pneumonia. SEC-1 is uncommon. The data suggest that there is some selective pressure for the SEC subtypes to be associated with certain human niches.

scholarly journals Vaginal Tampon Colonization by Staphylococcus aureus in Healthy Women

2020 ◽  
Vol 86 (18) ◽  
Author(s):  
Myriam Chiaruzzi ◽  
Alexia Barbry ◽  
Anaëlle Muggeo ◽  
Anne Tristan ◽  
Isaline Jacquemond ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Confidence Interval ◽  
Toxic Shock Syndrome ◽  
Intrauterine Device ◽  
Toxic Shock ◽  
Content Type ◽  
Healthy Women ◽  
High Prevalence ◽  
Menstruating Women ◽  
Toxic Shock Syndrome Toxin

ABSTRACT Tampons recovered from a cohort of 737 healthy women (median age, 32 years) were analyzed for the presence of Staphylococcus aureus. A total of 198 tampons (27%) were colonized by S. aureus, 28 (4%) by a strain producing toxic shock syndrome toxin 1 (TSST-1). S. aureus was detected more frequently in tampons that did not require an applicator for their insertion (74/233 [32%] versus 90/381 [24%]; odds ratio [OR] = 1.51 [95% confidence interval, 1.04 to 2.17]) and in women who used an intrauterine device for contraception (53/155 [34%] versus 145/572 [27%]; OR = 1.53 [95% confidence interval, 1.05 to 2.24]). The S. aureus strains isolated from tampons belonged to 22 different clonal complexes (CCs). The most prevalent CC was CC398 agr1 (n = 57 [27%]), a clone that does not produce superantigenic toxins, followed by CC30 agr3 (n = 27, 13%), producing TSST-1 (24/27 [89%]), the principal clone of S. aureus involved in menstrual toxic shock syndrome (MTSS). IMPORTANCE Menstrual toxic shock syndrome (MTSS) is an uncommon severe acute disease that occurs in healthy menstruating women colonized by TSST-1-producing S. aureus who use intravaginal protection, such as tampons and menstrual cups. The catamenial product collected by the protection serves as a growth medium for S. aureus and allows TSST-1 production. Previous studies evaluated the prevalence of genital colonization by S. aureus by vaginal swabbing, but they did not examine tampon colonization. This study demonstrated a high prevalence of tampon colonization by S. aureus and the presence of the CC30 TSST-1 S. aureus clone responsible for MTSS in tampons from healthy women. The results support the vaginal carriage of this lineage in healthy women. In addition, the higher prevalence of S. aureus within tampons that do not require an applicator indicates a crucial role for handwashing before tampon handling to decrease the risk of tampon contamination.

scholarly journals Device-Associated Menstrual Toxic Shock Syndrome

2020 ◽  
Vol 33 (3) ◽  
Author(s):  
Patrick M. Schlievert ◽  
Catherine C. Davis
Keyword(s):  
Risk Factors ◽  
Staphylococcus Aureus ◽  
Toxic Shock Syndrome ◽  
Immune Status ◽  
Human Populations ◽  
Toxic Shock ◽  
Content Type ◽  
Physician Awareness ◽  
First Time ◽  
Biomedical Community

SUMMARY In the 1980s, menstrual toxic shock syndrome (mTSS) became a household topic, particularly among mothers and their daughters. The research performed at the time, and for the first time, exposed the American public as well as the biomedical community, in a major way, to understanding disease progression and investigation. Those studies led to the identification of the cause, Staphylococcus aureus and the pyrogenic toxin superantigen TSS toxin 1 (TSST-1), and many of the risk factors, for example, tampon use. Those studies in turn led to TSS warning labels on the outside and inside of tampon boxes and, as important, uniform standards worldwide of tampon absorbency labeling. This review addresses our understanding of the development and conclusions related to mTSS and risk factors. We leave the final message that even though mTSS is not commonly in the news today, cases continue to occur. Additionally, S. aureus strains cycle in human populations in roughly 10-year intervals, possibly dependent on immune status. TSST-1-producing S. aureus bacteria appear to be reemerging, suggesting that physician awareness of this emergence and mTSS history should be heightened.

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

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Hema Sharma ◽  
Claire E. Turner ◽  
Matthew K. Siggins ◽  
Mona El-Bahrawy ◽  
Bruno Pichon ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Soft Tissue ◽  
Toxic Shock Syndrome ◽  
Soft Tissues ◽  
Toxic Shock ◽  
Content Type ◽  
Human Immune ◽  
Toxic Shock Syndrome Toxin ◽  
Draining Lymph Nodes

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.

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