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1.
mSphere ; 9(7): e0050524, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-38990001

ABSTRACT

During surveillance of Staphylococcus aureus in lesions from patients with atopic dermatitis (AD), we isolated Staphylococcus argenteus, a species registered in 2011 as a new member of the genus Staphylococcus and previously considered a lineage of S. aureus. Genome sequence comparisons between S. argenteus isolates and representative S. aureus clinical isolates from various origins revealed that the S. argenteus genome from AD patients closely resembles that of S. aureus causing skin infections. We previously reported that 17%-22% of S. aureus isolated from skin infections produce staphylococcal enterotoxin Y (SEY), which predominantly induces T-cell proliferation via the T-cell receptor (TCR) Vα pathway. Complete genome sequencing of S. argenteus isolates revealed a gene encoding a protein similar to superantigen SEY, designated as SargEY, on its chromosome. Population structure analysis of S. argenteus revealed that these isolates are ST2250 lineage, which was the only lineage positive for the SEY-like gene among S. argenteus. Recombinant SargEY demonstrated immunological cross-reactivity with anti-SEY serum. SargEY could induce proliferation of human CD4+ and CD8+ T cells, as well as production of TNF-α and IFN-γ. SargEY showed emetic activity in a marmoset monkey model. SargEY and SET (a phylogenetically close but uncharacterized SE) revealed their dependency on TCR Vα in inducing human T-cell proliferation. Additionally, TCR sequencing revealed other previously undescribed Vα repertoires induced by SEH. SargEY and SEY may play roles in exacerbating the respective toxin-producing strains in AD. IMPORTANCE: Staphylococcus aureus is frequently isolated from active lesions of atopic dermatitis (AD) patients. We reported that 17%-22% of S. aureus isolated from AD patients produced a novel superantigen staphylococcal enterotoxin Y (SEY). Unlike many S. aureus superantigens that activate T cells via T-cell receptor (TCR) Vß, SEY activates T cells via TCR Vα and stimulates cytokine secretion. Staphylococcus argenteus was isolated from AD patients during the surveillance for S. aureus. Phylogenetic comparison of the genome indicated that the isolate was very similar to S. aureus causing skin infections. The isolate encoded a SEY-like protein, designated SargEY, which, like SEY, activated T cells via the TCR Vα. ST2250 is the only lineage positive for SargEY gene. ST2250 S. argenteus harboring a superantigen SargEY gene may be a novel staphylococcal clone that infects human skin and is involved in the exacerbation of AD.


Subject(s)
Dermatitis, Atopic , Enterotoxins , Genome, Bacterial , Staphylococcus , Superantigens , Humans , Dermatitis, Atopic/microbiology , Dermatitis, Atopic/immunology , Superantigens/genetics , Superantigens/immunology , Staphylococcus/genetics , Staphylococcus/immunology , Staphylococcus/classification , Enterotoxins/genetics , Enterotoxins/immunology , Animals , Phylogeny , Genomics , Whole Genome Sequencing , Staphylococcal Infections/microbiology , Staphylococcal Infections/immunology
2.
Korean J Intern Med ; 39(4): 659-667, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38986495

ABSTRACT

BACKGROUND/AIMS: Sensitization to staphylococcal superantigens (SAgs) could contribute to asthma severity. However, its relevance with eosinophilic phenotype has not yet been clarified. This study aimed to investigate associations between serum specific IgE levels to SAg and eosinophilic airway inflammation in adult asthmatics. METHODS: The serum specific IgE levels to 3 SAgs, including staphylococcal enterotoxin A (SEA) and B (SEB), and toxic shock syndrome toxin-1 (TSST-1) were measured by ImmunoCAP in 230 adult asthmatic patients and 50 healthy controls (HCs). Clinical characteristics and laboratory parameters, including serum total/free IgE, and 2 eosinophil-activation markers, eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN), were analyzed according to blood eosinophil counts (BEC; 150 cells/µL) and serum specific IgE levels to 3 SAgs (0.35 kU/L). RESULTS: Asthmatic patients showed higher serum specific IgE levels to 3 SAgs than HCs (p < 0.05 for all). The serum total/clinfree IgE levels were significantly higher in asthmatics with positive IgE responses to 3 SAgs than those without (p < 0.05 for all). There were no significant differences in clinical parameters including age, asthma severity, comorbidities, or smoking according to IgE responses to 3 SAgs. Patients with positive IgE responses to SEB (not to SEA/TSST-1) had higher serum specific IgE levels to house dust mites and ECP/EDN as well as higher BEC with positive correlations between serum SEB-specific IgE levels and BEC/ECP/EDN (p < 0.05 for all). CONCLUSION: These findings suggest that serum SEB-specific IgE levels could contribute to eosinophil activation as well as IgE production in adult asthma.


Subject(s)
Asthma , Enterotoxins , Eosinophils , Immunoglobulin E , Phenotype , Superantigens , Humans , Enterotoxins/immunology , Immunoglobulin E/blood , Male , Asthma/immunology , Asthma/blood , Asthma/diagnosis , Female , Middle Aged , Adult , Eosinophils/immunology , Case-Control Studies , Superantigens/immunology , Superantigens/blood , Biomarkers/blood , Aged , Eosinophilia/immunology , Eosinophilia/blood , Eosinophilia/diagnosis , Eosinophil Cationic Protein/blood , Bacterial Toxins/immunology , Bacterial Toxins/blood , Eosinophil-Derived Neurotoxin/blood
3.
Int J Mol Sci ; 25(13)2024 Jul 07.
Article in English | MEDLINE | ID: mdl-39000566

ABSTRACT

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.


Subject(s)
CD4-Positive T-Lymphocytes , Lymphocyte Activation , Piperidines , Pyrimidines , Shock, Septic , Staphylococcal Infections , Th1 Cells , Animals , Piperidines/pharmacology , Piperidines/therapeutic use , Th1 Cells/immunology , Th1 Cells/drug effects , Th1 Cells/metabolism , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Shock, Septic/drug therapy , Shock, Septic/immunology , Shock, Septic/chemically induced , Mice , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Lymphocyte Activation/drug effects , Staphylococcal Infections/drug therapy , Staphylococcal Infections/immunology , Staphylococcal Infections/microbiology , Enterotoxins , Staphylococcus aureus/drug effects , Cytokines/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Mice, Inbred C57BL , Female , Disease Models, Animal , Superantigens/immunology
4.
J Clin Microbiol ; 62(8): e0063724, 2024 Aug 14.
Article in English | MEDLINE | ID: mdl-38990040

ABSTRACT

As a potential side effect of the severe acute respiratory syndrome coronavirus type 2 pandemic, invasive group A Streptococcus (iGAS) infections in Europe have increased dramatically in both children and adults in the end of 2022. This epidemiological and molecular study describes the distributions of streptococcal genes encoding the M antigen (emm types) and superantigens in patients with invasive and non-invasive GAS infections. From December 2022 to December 2023, a total of 163 GAS isolates were collected from sterile and non-sterile sites of patients at five hospitals in Germany including two tertiary care centers. Genes encoding M protein and superantigens were determined following the guidelines of CDC Streptococcus laboratory. Patients' characteristics were reviewed retrospectively. Correlations of clinical factors, emm types, and superantigens with rates of invasive infections were analyzed. Of the 163 included GAS cases, 112 (69%) were considered as invasive. In total, 33 different emm types were observed, of which emm1.0 (n = 49; 30%), emm89.0 (n = 15; 9%), and emm12.0 (n = 14; 9%) were most prevalent. In total, 70% of emm1.0 isolates belonged to M1UK lineage. No difference in invasive infections was observed for the M1UK lineage compared with other emm1.0 isolates. However, the emm1.0 type, presence of speA1-3, speG, or speJ, as well as adulthood were significantly associated with invasive infections. In contrast, emm12.0 isolates were significantly less associated with invasive infections. Multivariable analysis confirmed a significant influence of speJ and adulthood on iGAS infections. This study underlines the importance of continuous monitoring of genomic trends and identification of emerging GAS variants. This may aid in delineating pathogenicity factors of Streptococcus pyogenes that propel invasive infections.


Subject(s)
Antigens, Bacterial , Bacterial Outer Membrane Proteins , Carrier Proteins , Streptococcal Infections , Streptococcus pyogenes , Humans , Streptococcal Infections/microbiology , Streptococcal Infections/epidemiology , Streptococcus pyogenes/genetics , Streptococcus pyogenes/classification , Streptococcus pyogenes/isolation & purification , Germany/epidemiology , Retrospective Studies , Bacterial Outer Membrane Proteins/genetics , Adult , Female , Male , Middle Aged , Child , Antigens, Bacterial/genetics , Carrier Proteins/genetics , Adolescent , Child, Preschool , Aged , Young Adult , Infant , Superantigens/genetics , Aged, 80 and over
5.
Hum Vaccin Immunother ; 20(1): 2360338, 2024 Dec 31.
Article in English | MEDLINE | ID: mdl-38857905

ABSTRACT

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138-147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Enterotoxins , Enterotoxins/immunology , Enterotoxins/antagonists & inhibitors , Humans , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Animals , Crystallography, X-Ray , Staphylococcus aureus/immunology , Staphylococcal Infections/immunology , Staphylococcal Infections/prevention & control , Epitopes, B-Lymphocyte/immunology , Mice , Shock, Septic/immunology , Shock, Septic/prevention & control , Female , Leukocytes, Mononuclear/immunology , Staphylococcal Vaccines/immunology , Antibodies, Bacterial/immunology , Superantigens/immunology
6.
Acta Derm Venereol ; 104: adv34882, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38860624

ABSTRACT

Patients with atopic dermatitis (AD) are more likely than healthy individuals to harbour Staphylococcus aureus on their skin. Superantigens (SAgs) produced by specific S. aureus strains may contribute to AD-associated skin inflammation. The present study compared the prevalence and types of SAg-encoding genes between S. aureus isolated from patients with AD and from  controls, and within the AD group between isolates from different sampling sites (lesional skin, non-lesional skin, and nares). This retrospective case-control study extracted data from 2 previous studies that examined S. aureus using whole-genome sequencing. The 138 S. aureus isolates obtained from 71 AD patients contained 349 SAg-encoding genes; 22 (6.3%) were found in isolates from nares (0.4 ± 0.6 genes per isolate), 99 (28.4%) in isolates from non-lesional skin (3.7 ± 3.9), and 228 (65.3%) in isolates from lesional skin (4.2 ± 4.5). S. aureus (n = 101) from the control group contained 594 SAg-encoding genes (5.9 ± 4.2). Of the S. aureus isolated from lesional AD skin, 69% carried at least 1 gene encoding SAg compared with 33% of AD nasal isolates. SAg could be a factor in the pathogenesis of a subset of AD patients.


Subject(s)
Dermatitis, Atopic , Skin , Staphylococcus aureus , Superantigens , Humans , Dermatitis, Atopic/microbiology , Superantigens/genetics , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Retrospective Studies , Skin/microbiology , Male , Female , Case-Control Studies , Adult , Staphylococcal Skin Infections/microbiology , Middle Aged , Young Adult
7.
J Biol Chem ; 300(7): 107455, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38852884

ABSTRACT

Menstrual toxic shock syndrome (mTSS) is a rare but severe disorder associated with the use of menstrual products such as high-absorbency tampons and is caused by Staphylococcus aureus strains that produce the toxic shock syndrome toxin-1 (TSST-1) superantigen. Herein, we screened a library of 3920 small bioactive molecules for the ability to inhibit transcription of the TSST-1 gene without inhibiting the growth of S. aureus. The dominant positive regulator of TSST-1 is the SaeRS two-component system (TCS), and we identified phenazopyridine hydrochloride (PP-HCl) that repressed the production of TSST-1 by inhibiting the kinase function of SaeS. PP-HCl competed with ATP for binding of the kinase SaeS leading to decreased phosphorylation of SaeR and reduced expression of TSST-1 as well as several other secreted virulence factors known to be regulated by SaeRS. PP-HCl targets the virulence of S. aureus, and it also decreases the impact of TSST-1 on human lymphocytes without affecting the healthy vaginal microbiota. Our findings demonstrate the promising potential of PP-HCl as a therapeutic strategy against mTSS.


Subject(s)
Bacterial Proteins , Bacterial Toxins , Enterotoxins , Staphylococcus aureus , Superantigens , Superantigens/metabolism , Superantigens/genetics , Enterotoxins/metabolism , Staphylococcus aureus/drug effects , Staphylococcus aureus/metabolism , Humans , Bacterial Toxins/metabolism , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/antagonists & inhibitors , Female , Shock, Septic/drug therapy , Shock, Septic/metabolism , Shock, Septic/microbiology , Gene Expression Regulation, Bacterial/drug effects , Protein Kinases/metabolism , Protein Kinases/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Staphylococcal Infections/drug therapy , Staphylococcal Infections/metabolism , Staphylococcal Infections/microbiology , Virulence/drug effects , Lymphocytes/metabolism , Lymphocytes/drug effects , Menstrual Hygiene Products
8.
FEMS Microbiol Lett ; 3712024 Jan 09.
Article in English | MEDLINE | ID: mdl-38806245

ABSTRACT

Streptococcus pyogenes is a significant human pathogen, producing a range of virulence factors, including streptococcal pyrogenic exotoxin B (SpeB) that is associated with foodborne outbreaks. It was only known that this cysteine protease mediates cleavage of transmembrane proteins to permit bacterial penetration and is found in 25% of clinical isolates from streptococcal toxic shock syndrome patients with extreme inflammation. Its interaction with host and streptococcal proteins has been well characterized, but doubt remains about whether it constitutes a superantigen. In this study, for the first time it is shown that SpeB acts as a superantigen, similarly to other known superantigens such as staphylococcal enterotoxin A or streptococcal pyrogenic exotoxin type C, by inducing proliferation of murine splenocytes and cytokine secretion, primarily of interleukin-2 (IL-2), as shown by cytometric bead array analysis. IL-2 secretion was confirmed by enzyme-linked immunosorbent assay (ELISA) as well as secretion of interferon-γ. ELISA showed a dose-dependent relationship between SpeB concentration in splenocyte cells and IL-2 secretion levels, and it was shown that SpeB retains activity in milk pasteurized for 30 min at 63°C.


Subject(s)
Bacterial Proteins , Cell Proliferation , Exotoxins , Interferon-gamma , Interleukin-2 , Spleen , Streptococcus pyogenes , Superantigens , Animals , Interleukin-2/metabolism , Superantigens/immunology , Superantigens/metabolism , Exotoxins/metabolism , Exotoxins/immunology , Interferon-gamma/metabolism , Interferon-gamma/immunology , Mice , Spleen/microbiology , Spleen/cytology , Spleen/immunology , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Streptococcus pyogenes/immunology , Streptococcus pyogenes/metabolism , Female , Mice, Inbred BALB C
9.
J Korean Med Sci ; 39(17): e154, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38711318

ABSTRACT

The emergence of invasive infections attributed to group A Streptococcus (GAS) infections, has resurged since the 1980s. The recent surge in reports of toxic shock syndrome due to GAS in Japan in 2024, while sensationalized in the media, does not represent a novel infectious disease per se, as its diagnosis, treatment, and prevention are already well-established. However, due to signs of increasing incidence since 2011, further research is needed. Health authorities in neighboring countries like The Republic of Korea should not only issue travel advisories but also establish meticulous surveillance systems and initiate epidemiological studies on the genotypic variations of this disease while awaiting various epidemiological research findings from Japan.


Subject(s)
Shock, Septic , Streptococcal Infections , Streptococcus pyogenes , Humans , Shock, Septic/microbiology , Streptococcus pyogenes/isolation & purification , Streptococcus pyogenes/genetics , Streptococcal Infections/microbiology , Streptococcal Infections/diagnosis , Republic of Korea , Japan , Superantigens/genetics , Anti-Bacterial Agents/therapeutic use , Enterotoxins/genetics
10.
Immunol Cell Biol ; 102(5): 365-380, 2024.
Article in English | MEDLINE | ID: mdl-38572664

ABSTRACT

Staphylococcus aureus is a significant bacterial pathogen in both community and hospital settings, and the escalation of antimicrobial-resistant strains is of immense global concern. Vaccination is an inviting long-term strategy to curb staphylococcal disease, but identification of an effective vaccine has proved to be challenging. Three well-characterized, ubiquitous, secreted immune evasion factors from the staphylococcal superantigen-like (SSL) protein family were selected for the development of a vaccine. Wild-type SSL3, 7 and 11, which inhibit signaling through Toll-like receptor 2, cleavage of complement component 5 and neutrophil function, respectively, were successfully combined into a stable, active fusion protein (PolySSL7311). Vaccination of mice with an attenuated form of the PolySSL7311 protein stimulated significantly elevated specific immunoglobulin G and splenocyte proliferation responses to each component relative to adjuvant-only controls. Vaccination with PolySSL7311, but not a mixture of the individual proteins, led to a > 102 reduction in S. aureus tissue burden compared with controls after peritoneal challenge. Comparable antibody responses were elicited after coadministration of the vaccine in either AddaVax (an analog of MF59) or an Alum-based adjuvant; but only AddaVax conferred a significant reduction in bacterial load, aligning with other studies that suggest both cellular and humoral immune responses are necessary for protective immunity to S. aureus. Anti-sera from mice immunized with PolySSL7311, but not individual proteins, partially neutralized the functional activities of SSL7. This study confirms the importance of these SSLs for the survival of S. aureus in vivo and suggests that PolySSL7311 is a promising vaccine candidate.


Subject(s)
Bacterial Proteins , Staphylococcal Infections , Staphylococcal Vaccines , Staphylococcus aureus , Superantigens , Animals , Staphylococcus aureus/immunology , Staphylococcal Vaccines/immunology , Superantigens/immunology , Staphylococcal Infections/immunology , Staphylococcal Infections/prevention & control , Mice , Bacterial Proteins/immunology , Antibodies, Bacterial/immunology , Antibodies, Bacterial/blood , Female , Recombinant Fusion Proteins/immunology , Immunoglobulin G/immunology , Immunoglobulin G/blood , Feasibility Studies , Vaccination , Antigens, Bacterial/immunology , Mice, Inbred BALB C , Adjuvants, Immunologic
11.
Front Immunol ; 15: 1365074, 2024.
Article in English | MEDLINE | ID: mdl-38510259

ABSTRACT

Staphylococcus aureus is a gram-positive bacterium that may cause intestinal inflammation by secreting enterotoxins, which commonly cause food-poisoning and gastrointestinal injuries. Staphylococcal enterotoxin B (SEB) acts as a superantigen (SAg) by binding in a bivalent manner the T-cell receptor (TCR) and the costimulatory receptor CD28, thus stimulating T cells to produce large amounts of inflammatory cytokines, which may affect intestinal epithelial barrier integrity and functions. However, the role of T cell-mediated SEB inflammatory activity remains unknown. Here we show that inflammatory cytokines produced by T cells following SEB stimulation induce dysfunctions in Caco-2 intestinal epithelial cells by promoting actin cytoskeleton remodelling and epithelial cell-cell junction down-regulation. We also found that SEB-activated inflammatory T cells promote the up-regulation of epithelial-mesenchymal transition transcription factors (EMT-TFs) in a nuclear factor-κB (NF-κB)- and STAT3-dependent manner. Finally, by using a structure-based design approach, we identified a SEB mimetic peptide (pSEB116-132) that, by blocking the binding of SEB to CD28, dampens inflammatory-mediated dysregulation of intestinal epithelial barrier.


Subject(s)
CD28 Antigens , Superantigens , Humans , Caco-2 Cells , Enterotoxins , Cytokines
12.
Genes Cells ; 29(5): 397-416, 2024 May.
Article in English | MEDLINE | ID: mdl-38454012

ABSTRACT

Staphylococcus aureus is a noteworthy pathogen in allergic diseases, as four staphylococcal exotoxins activate mast cells, a significant contributor to inflammation, in an IgE-independent manner. Although the adhesion of mast cells is an essential process for their immune responses, only a small number of exotoxins have been reported to affect the process. Here, we demonstrated that staphylococcal superantigen-like (SSL) 3, previously identified as a toll-like receptor 2 agonist, induced the adhesion of murine bone marrow-derived mast cells to culture substratum. SSL3-induced adhesion was mediated by fibronectin in an Arg-Gly-Asp (RGD) sequence-dependent manner, suggesting the integrins were involved in the process. Additionally, SSL3 was found to bind to an anti-adhesive surface protein CD43. SSL3 induced the adhesion of HEK293 cells expressing exogenous CD43, suggesting that CD43 is the target molecule for adhesion induced by SSL3. Evaluation of SSL3-derived mutants showed that the C-terminal region (253-326), specifically T285 and H307, are necessary to induce adhesion. SSL3 augmented the IL-13 production of mast cells in response to immunocomplex and SSL12. These findings reveal a novel function of SSL3, triggering cell adhesion and enhancing mast cell activation. This study would clarify the correlation between S. aureus and allergic diseases such as atopic dermatitis.


Subject(s)
Cell Adhesion , Leukosialin , Mast Cells , Staphylococcus aureus , Superantigens , Animals , Mast Cells/metabolism , Mast Cells/immunology , Mice , Humans , Superantigens/metabolism , Staphylococcus aureus/metabolism , Staphylococcus aureus/immunology , HEK293 Cells , Leukosialin/metabolism , Bacterial Proteins/metabolism , Interleukin-13/metabolism , Mice, Inbred C57BL
13.
Angew Chem Int Ed Engl ; 63(21): e202317552, 2024 05 21.
Article in English | MEDLINE | ID: mdl-38497459

ABSTRACT

Celiac disease (CeD) is an autoimmune disorder triggered by gluten proteins, affecting approximately 1 % of the global population. The 33-mer deamidated gliadin peptide (DGP) is a metabolically modified wheat-gluten superantigen for CeD. Here, we demonstrate that the 33-mer DGP spontaneously assembles into oligomers with a diameter of approximately 24 nm. The 33-mer DGP oligomers present two main secondary structural motifs-a major polyproline II helix and a minor ß-sheet structure. Importantly, in the presence of 33-mer DGP oligomers, there is a statistically significant increase in the permeability in the gut epithelial cell model Caco-2, accompanied by the redistribution of zonula occludens-1, a master tight junction protein. These findings provide novel molecular and supramolecular insights into the impact of 33-mer DGP in CeD and highlight the relevance of gliadin peptide oligomerization.


Subject(s)
Celiac Disease , Enterocytes , Gliadin , Humans , Celiac Disease/metabolism , Celiac Disease/pathology , Caco-2 Cells , Gliadin/chemistry , Gliadin/metabolism , Enterocytes/metabolism , Superantigens/chemistry , Superantigens/metabolism , Permeability
14.
Clin Microbiol Infect ; 30(6): 779-786, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38408643

ABSTRACT

OBJECTIVES: Globally, the isolation of community-associated methicillin-resistant Staphylococcus aureus (MRSA) harbouring both the Panton-Valentine leucocidin (PVL) and toxic shock syndrome toxin 1 (TSST-1) genes is rare. However, we encountered an outbreak of the ST22-PT clone exhibiting this phenotype in Japan. Notably, the TSST-1 gene was duplicated in most of the strains. This study aimed to elucidate the mechanisms underlying this gene duplication. METHODS: A total of 90 MRSA isolates were collected from the skin of outpatients in Fukuoka City, Japan, between 2017 and 2019. Whole-genome sequencing was performed on MRSA strains that were PVL and TSST-1 positive. RESULTS: A total of 43 (47.8%) strains produced TSST-1, 20 (22.2%) produced PVL, and 16 (17.8%) produced both. Fifteen isolates were classified as ST22/SCCmec type IVa (ST22-PT clone) and one as ST1/SCCmec type V (ST1-PT clone). Three distinct ST22-PT clones were identified: Fukuoka clone I (one PVL gene and one TSST-1 gene), Fukuoka clone II (addition of a TSST-1 gene to Fukuoka clone I), and Fukuoka clone III (marked by a chromosomal inversion in a large region from Fukuoka clone II). DISCUSSION: Fukuoka clone I may have integrated a novel pathogenicity island bearing the TSST-1 gene, leading to the emergence of Fukuoka clone II with a duplicated TSST-1 gene. This duplication subsequently instigated a chromosomal inversion in a large region owing to the homologous sequence surrounding TSST-1, giving rise to Fukuoka clone III. These findings provide crucial insights into the genetic evolution of MRSA.


Subject(s)
Bacterial Toxins , Enterotoxins , Exotoxins , Leukocidins , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Superantigens , Superantigens/genetics , Bacterial Toxins/genetics , Exotoxins/genetics , Enterotoxins/genetics , Leukocidins/genetics , Humans , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcal Infections/microbiology , Japan/epidemiology , Whole Genome Sequencing , Gene Duplication , Male , Female , Middle Aged , Aged , Disease Outbreaks , Evolution, Molecular , Adult , Community-Acquired Infections/microbiology
15.
J Bacteriol ; 206(3): e0044723, 2024 03 21.
Article in English | MEDLINE | ID: mdl-38334326

ABSTRACT

Menstrual toxic shock syndrome (mTSS) is a rare but life-threatening disease associated with the use of high-absorbency tampons. The production of the Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1) superantigen is involved in nearly all cases of mTSS and is tightly controlled by regulators responding to the environment. In the prototypic mTSS strain S. aureus MN8, the major repressor of TSST-1 is the carbon catabolite protein A (CcpA), which responds to glucose concentrations in the vaginal tract. Healthy vaginal Lactobacillus species also depend on glucose for both growth and acidification of the vaginal environment through lactic acid production. We hypothesized that interactions between the vaginal microbiota [herein referred to as community state types (CSTs)] and S. aureus MN8 depend on environmental cues and that these interactions subsequently affect TSST-1 production. Using S. aureus MN8 ΔccpA growing in various glucose concentrations, we demonstrate that the supernatants from different CSTs grown in vaginally defined medium (VDM) could significantly decrease tst expression. When co-culturing CST species with MN8 ∆ccpA, we show that Lactobacillus jensenii completely inhibits TSST-1 production in conditions mimicking healthy menstruation or mTSS. Finally, we show that growing S. aureus in "unhealthy" or "transitional" CST supernatants results in higher interleukin 2 (IL-2) production from T cells. These findings suggest that dysbiotic CSTs may encourage TSST-1 production in the vaginal tract and further indicate that the CSTs are likely important for the protection from mTSS.IMPORTANCEIn this study, we investigate the impact of the vaginal microbiota against Staphylococcus aureus in conditions mimicking the vaginal environment at various stages of the menstrual cycle. We demonstrate that Lactobacillus jensenii can inhibit toxic shock syndrome toxin-1 (TSST-1) production, suggesting the potential for probiotic activity in treating and preventing menstrual toxic shock syndrome (mTSS). On the other side of the spectrum, "unhealthy" or "transient" bacteria such as Gardnerella vaginalis and Lactobacillus iners support more TSST-1 production by S. aureus, suggesting that community state types are important in the development of mTSS. This study sets forward a model for examining contact-independent interactions between pathogenic bacteria and the vaginal microbiota. It also demonstrates the necessity of replicating the environment when studying one as dynamic as the vagina.


Subject(s)
Bacterial Toxins , Lactobacillus , Shock, Septic , Staphylococcal Infections , Female , Humans , Staphylococcus aureus/metabolism , Shock, Septic/microbiology , Cues , Enterotoxins/metabolism , Superantigens/metabolism , Vagina/microbiology , Bacteria/metabolism , Staphylococcal Infections/microbiology , Glucose/metabolism
16.
Nat Rev Immunol ; 24(6): 417-434, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38225276

ABSTRACT

Bacterial T cell superantigens (SAgs) are a family of microbial exotoxins that function to activate large numbers of T cells simultaneously. SAgs activate T cells by direct binding and crosslinking of the lateral regions of MHC class II molecules on antigen-presenting cells with T cell receptors (TCRs) on T cells; these interactions alter the normal TCR-peptide-MHC class II architecture to activate T cells in a manner that is independent of the antigen specificity of the TCR. SAgs have well-recognized, central roles in human diseases such as toxic shock syndrome and scarlet fever through their quantitative effects on the T cell response; in addition, numerous other consequences of SAg-driven T cell activation are now being recognized, including direct roles in the pathogenesis of endocarditis, bloodstream infections, skin disease and pharyngitis. In this Review, we summarize the expanding family of bacterial SAgs and how these toxins can engage highly diverse adaptive immune receptors. We highlight recent findings regarding how SAg-driven manipulation of the adaptive immune response may operate in multiple human diseases, as well as contributing to the biology and life cycle of SAg-producing bacterial pathogens.


Subject(s)
Receptors, Antigen, T-Cell , Superantigens , T-Lymphocytes , Superantigens/immunology , Humans , T-Lymphocytes/immunology , Receptors, Antigen, T-Cell/immunology , Antigens, Bacterial/immunology , Lymphocyte Activation/immunology , Animals , Histocompatibility Antigens Class II/immunology , Bacteria/immunology
17.
Article in English | MEDLINE | ID: mdl-38176845

ABSTRACT

OBJECTIVES: To study the genomic epidemiology of Streptococcus pyogenes causing bloodstream infections (GAS-BSI) in a Spanish tertiary hospital during the United Kingdom invasive S. pyogenes outbreak alert. METHODS: Retrospective epidemiological analysis of GAS-BSI during the January-May 2017-2023 period. WGS was performed using Ion torrent GeneStudio™ S5 system for emm typing and identification of superantigen genes in S. pyogenes isolated during the 2022-2023 UK outbreak alert. RESULTS: During 2023, there were more cases of GAS-BSI compared to the same period of previous year with a non-significant increase in children. Fourteen isolates were sequenced. The emm1 (6/14, 42.9%) and emm12 (2/14, 14.3%) types predominated; 5 of 6 (75%) emm1 isolates were from the M1UK clone. The most detected superantigen genes were speG (12/14, 85.7%), speC (10/14, 71.4%), speJ (7/14, 50%), and speA (5/15, 33.3%). speA and speJ were predominant in M1UK clone. CONCLUSIONS: Our genomic epidemiology in 2023 is similar to the reported data from the UK outbreak alert in the same period and different from previous national S. pyogenes surveillance reports.


Subject(s)
Streptococcal Infections , Streptococcus pyogenes , Child , Humans , Streptococcus pyogenes/genetics , Retrospective Studies , Tertiary Care Centers , Antigens, Bacterial/genetics , Streptococcal Infections/epidemiology , Superantigens/genetics , United Kingdom/epidemiology
18.
J Immunol Res ; 2024: 2313062, 2024.
Article in English | MEDLINE | ID: mdl-38268531

ABSTRACT

Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vß and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases.


Subject(s)
Antibodies , CD28 Antigens , Antigen-Presenting Cells , Peptides , Superantigens
19.
Trends Microbiol ; 32(3): 228-230, 2024 03.
Article in English | MEDLINE | ID: mdl-38182522

ABSTRACT

Staphylococcus aureus is a proficient colonizer and opportunistic pathogen which can lead to vaginal dysbiosis, aerobic vaginitis, or life-threatening menstrual toxic shock syndrome. Here we explore the complex but underappreciated interactions that S. aureus may impose on the vaginal environment leading to additional disease outcomes.


Subject(s)
Bacterial Toxins , Microbiota , Staphylococcal Infections , Female , Humans , Enterotoxins , Staphylococcus aureus , Superantigens
20.
Int J Biol Macromol ; 256(Pt 1): 128437, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38013079

ABSTRACT

Staphylococcus aureus has become a significant cause of health risks in humankind. Staphylococcal superantigens (SAgs) or enterotoxins are the key virulent factors that can exhibit acute diseases to severe life-threatening conditions. Recent literature reports S. aureus has steadily gained new enterotoxin genes over the past few decades. In spite of current knowledge of the established SAgs, several questions on putative enterotoxins are still remaining unanswered. Keeping that in mind, this study sheds light on a putative enterotoxin SEl26 to characterize its structural and functional properties. In-silico analyses indicate its close relation with the conventional SAgs, especially the zinc-binding SAgs. Additionally, important residues that are vital for the T-cell receptor (TcR) and major histocompatibility complex class II (MHC-II) interaction were predicted and compared with established SAgs. Besides, our biochemical analyses exhibited the binding of this putative enterotoxin with MHC-II, followed by regulating pro-inflammatory and anti-inflammatory cytokines.


Subject(s)
Enterotoxins , Staphylococcus aureus , Enterotoxins/genetics , Staphylococcus aureus/metabolism , Amino Acid Sequence , Binding Sites , Superantigens/genetics , Superantigens/metabolism , Staphylococcus , Histocompatibility Antigens Class II/genetics
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