Fracture biomechanics influence local and systemic immune responses in a murine fracture-related infection model.

Biomechanical stability plays an important role in fracture healing, with unstable fixation being associated with healing disturbances. A lack of stability is also considered a risk factor for fracture-related infection (FRI), although confirmatory studies and an understanding of the underlying mechanisms are lacking. In the present study, we investigate whether biomechanical (in)stability can lead to altered immune responses in mice under sterile or experimentally inoculated conditions. In non-inoculated C57BL/6 mice, instability resulted in an early increase of inflammatory markers such as granulocyte-colony stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin (IL)-6 within the bone. When inoculated with Staphylococcus epidermidis, instability resulted in a further significant increase in G-CSF, IL-6 and KC in bone tissue. Staphylococcus aureus infection led to rapid osteolysis and instability in all animals and was not further studied. Gene expression measurements also showed significant upregulation in CCL2 and G-CSF in these mice. IL-17A was found to be upregulated in all S. epidermidis infected mice, with higher systemic IL-17A cell responses in mice that cleared the infection, which was found to be produced by CD4+ and γδ+ T cells in the bone marrow. IL-17A knock-out (KO) mice displayed a trend of delayed clearance of infection (P=0.22, Fisher's exact test) and an increase in interferon (IFN)-γ production. Biomechanical instability leads to a more pronounced local inflammatory response, which is exaggerated by bacterial infection. This study provides insights into long-held beliefs that biomechanics are crucial not only for fracture healing, but also for control of infection.

Type III-A CRISPR immunity promotes mutagenesis of staphylococci.

Horizontal gene transfer and mutation are the two major drivers of microbial evolution that enable bacteria to adapt to fluctuating environmental stressors1. Clustered, regularly interspaced, short palindromic repeats (CRISPR) systems use RNA-guided nucleases to direct sequence-specific destruction of the genomes of mobile genetic elements that mediate horizontal gene transfer, such as conjugative plasmids2 and bacteriophages3, thus limiting the extent to which bacteria can evolve by this mechanism. A subset of CRISPR systems also exhibit non-specific degradation of DNA4,5; however, whether and how this feature affects the host has not yet been examined. Here we show that the non-specific DNase activity of the staphylococcal type III-A CRISPR-Cas system increases mutations in the host and accelerates the generation of antibiotic resistance in Staphylococcus aureus and Staphylococcus epidermidis. These mutations require the induction of the SOS response to DNA damage and display a distinct pattern. Our results demonstrate that by differentially affecting both mechanisms that generate genetic diversity, type III-A CRISPR systems can modulate the evolution of the bacterial host.

Cell Immunity in Implant-Associated Infections Caused by Biofilm-Forming Microorganisms.

High biofilm-forming capacity of Staphylococcus spp. strains isolated from biomaterial of patients with infectious complications after primary knee replacement developed within 6-12 months after surgery was experimentally demonstrated. Differential leukocyte counts and some indicators of cell immunity in these patients were compared with those in patients without purulent complications and healthy volunteers. In patients with implant-associated infection, the relative numbers of T cells (both T-helpers and T-suppressors) B cells were significantly (p<0.05) reduced, while the number of NK cells was significantly increased in comparison with the corresponding parameters in other groups. The revealed changes attest to cell immunity failure in biofilm infection.

The Card1 nuclease provides defence during type III CRISPR immunity.

In the type III CRISPR-Cas immune response of prokaryotes, infection triggers the production of cyclic oligoadenylates that bind and activate proteins that contain a CARF domain1,2. Many type III loci are associated with proteins in which the CRISPR-associated Rossman fold (CARF) domain is fused to a restriction  endonuclease-like domain3,4. However, with the exception of the well-characterized Csm6 and Csx1 ribonucleases5,6, whether and how these inducible effectors provide defence is not known. Here we investigated a type III CRISPR accessory protein, which we name cyclic-oligoadenylate-activated single-stranded ribonuclease and single-stranded deoxyribonuclease 1 (Card1). Card1 forms a symmetrical dimer that has a large central cavity between its CRISPR-associated Rossmann fold and restriction endonuclease domains that binds cyclic tetra-adenylate. The binding of ligand results in a conformational change comprising the rotation of individual monomers relative to each other to form a more compact dimeric scaffold, in which a manganese cation coordinates the catalytic residues and activates the cleavage of single-stranded-but not double-stranded-nucleic acids (both DNA and RNA). In vivo, activation of Card1 induces dormancy of the infected hosts to provide immunity against phage infection and plasmids. Our results highlight the diversity of strategies used in CRISPR systems to provide immunity.

Intramammary inoculation with lactic acid bacteria at dry-off triggers an immunomodulatory response in dairy cows.

The use of antibiotics to prevent bovine mastitis is responsible for the emergence and selection of resistant strains. Lactic acid bacteria (LAB) could be introduced into animal feed as an alternative prevention method that would bypass the risk of resistance development. In previous research, we demonstrated that two probiotic LAB strains isolated from bovine milk were capable of stimulating the production of antibodies and the host's immune cellular response in the udder. The present study aimed to elucidate whether the antibodies of animals inoculated with these strains were able to increase phagocytosis by neutrophils and inhibit the growth of different mastitis-causing pathogens. Moreover, the effect of LAB on the expression of pro-inflammatory cytokines was assessed. Ten animals were inoculated intramammarily with 106 cells of the two strains at dry-off. The blood serum was tested for its ability to opsonize bovine mastitis pathogens, the in vitro bactericidal activity of bovine blood and milk against these pathogens was determined, and cytokine mRNA expression was quantified in milk somatic cells. The inoculated animals did not show abnormal signs of sensitivity to the LAB. Their blood serum significantly enhanced the phagocytosis of Staphylococcus spp. and the LAB. Escherichia coli and Streptococcus uberis were inhibited by the milk serum but not the blood serum, whereas Staphylococcus aureus and Staphylococcus haemolyticus were inhibited by both. In regard to cytokine expression, interleukin (IL)-1ß increased markedly for up to 4 h post-inoculation, and an increase in IL-8 was observed 4, 12 and 24 h after inoculation. Tumour necrosis factor-α mRNA increased 1 and 2 h after inoculation and a significant difference was registered at 6 h for interferon-γ. This rapid immunomodulatory response shows that inoculating animals with LAB at dry-off, when they are especially susceptible, could be a useful strategy for the prevention of bovine mastitis.

Investigation of a Staphylococcus argenteus Strain Involved in a Chronic Prosthetic-Joint Infection.

Staphylococcus argenteus is an emerging species responsible for infections comparable to those induced by Staphylococcus aureus. It has been involved in few chronic or persistent infections so far. In this study, we described a case of a persistent prosthetic-joint infection (PJI) affecting a young woman. We investigated in vitro the virulence traits of the incriminated S. argenteus strain (bone cell invasion, biofilm formation and induction of inflammation) and analyzed its genome, in comparison with two other strains of S. argenteus and two S. aureus isolates. It appeared that this S. argenteus PJI strain combined biofilm formation, osteoblast invasion and intracellular persistence abilities together with genes potentially involved in the escape of the host immune defenses, which might explain the chronicization of the infection.

Inhibition of Host Arginase Activity Against Staphylococcal Bloodstream Infection by Different Metabolites.

Staphylococcus aureus is a notorious bacterial pathogen that often causes soft tissue and bloodstream infections and invariably garners resistance mechanisms against new antibiotics. Modulation of the host immune response by metabolites is a powerful tool against bacterial infections, but has not yet been used against S. aureus infections. In this study, we identified four metabolite biomarkers: L-proline, L-isoleucine, L-leucine, and L-valine (PILV), through a metabolomics study using animal models of S. aureus bloodstream infection. The exogenous administration of each metabolite or of PILV showed anti-infective effects, and a higher protection was achieved with PILV in comparison to individual metabolites. During the staphylococcal infection, the expression of most host arginase and nitric oxide synthase (NOS) isozymes was simultaneously induced in mouse liver, kidney, and blood samples. However, the induction of arginase isozymes was dramatically stronger than that of NOS isozymes. This elevated arginase activity was inhibited by the metabolite biomarkers thus killing S. aureus, and PILV exhibited the strongest inhibition of arginase activity and bacterial inhibition. The suppression of arginase activity also contributed to the metabolite-mediated phagocytic killing of S. aureus in mouse and human blood. Our findings demonstrate the metabolite-mediated arginase inhibition as a therapeutic intervention for S. aureus infection.

Measurement of Serum Anti-staphylococcal Antibodies Increases Positive Predictive Value of Preoperative Aspiration for Hip Prosthetic Joint Infection.

BACKGROUND: Preoperative synovial fluid culture is pivotal in the early diagnosis of prosthetic joint infection (PJI) but may yield false-positive and false-negative results. We evaluated the predictive value of synovial fluid culture results combined with the measurement of serum anti-staphylococcal antibodies (SASA). QUESTIONS/PURPOSES: (1) For hip and knee PJI, does combining positive SASA results with preoperative synovial culture results improve the positive predictive value (PPV) of preoperative synovial fluid culture alone? (2) Does combining preoperative synovial fluid culture results with a positive cell count and differential result increase the PPV of preoperative synovial fluid culture alone? (3) What proportion of isolated organisms exhibit concordance in antibiotic susceptibility: preoperative aspiration versus intraoperative isolates? METHODS: A prospective study was conducted at two French reference centers that manage bone and joint infections and included 481 adult patients who had a revision or resection arthroplasty between June 25, 2012 and June 23, 2014. Exclusion criteria including no serum sample available for immunoassay, the lack of microbiological documentation, and the absence of preoperative aspiration reduced the patient number to 353. Seven patients with an undetermined SASA result were excluded from the analysis. We also excluded patients with PJI involving more than one Staphylococcus species (polystaphylococcal infection) and those in whom more than one Staphylococcus species was recovered from the preoperative synovial fluid culture (polystaphylococcal synovial fluid culture). In total, 340 patients were included in the analysis (no infection, 67% [226 of 340]; staphylococcal infection, 21% [71 of 340]; other infection, 13% [43 of 340]). The preoperative synovial fluid analysis included a cell count and differential and bacterial culture. SASAs were measured using a multiplex immunoassay. The diagnosis of PJI was determined using the Infectious Diseases Society of America (IDSA) criteria [] and intraoperative tissue culture at the time of revision surgery was used as the gold standard (at least one positive intraoperative sample for a "virulent" organism (such as S. aureus) or two positive samples for a "non-virulent" (for example S. epidermidis). RESULTS: SASA increased the PPV compared with synovial fluid culture alone (92% [95% CI 82 to 97] versus 79% [95% CI 68 to 87]; p = 0.04); when stratified by site, an increase in PPV was seen in hip infections (100% [95% CI 89 to 100] versus 77% [95% CI 63 to 88]; p = 0.01) but not in knee infections (84% [95% CI 66 to 95] versus 80% [95% CI 64 to 91]; p = 0.75). A positive cell count and differential result increased the PPV of staphylococcal synovial fluid cultures compared with synovial fluid culture alone (86% [95% CI 70 to 95] versus 79% [95% CI 68 to 87]; p = 0.36); when stratified by site, no difference in hip and knee infections was observed (86% [95% CI 67 to 96] versus 77% [95% CI 63 to 88]; p = 0.42) and 86% [95% CI 70 to 95] versus 80% [95% CI 64 to 91]; p = 0.74). CONCLUSION: SASA measurement improves the predictive value of synovial fluid cultures of the hip for all staphylococcal organisms, including coagulase-negative staphylococci, but the PPV of SASA plus synovial fluid culture it is not superior to the PPV of synovial fluid cell count/differential plus synovial culture for the knee. LEVEL OF EVIDENCE: Level III, diagnostic study.

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.

Nasal Colonization by Staphylococci and Severity of Atopic Dermatitis.

BACKGROUND: Skin colonization by Staphylococcus aureus (SA) correlates with increased severity of atopic dermatitis (AD). The role of nasal SA carriage and coagulase-negative staphylococci (CNSs) in AD is unclear. OBJECTIVE: The aim of this study was to assess the influence of colonization of lesional/nonlesional skin and the anterior nares by SA and CNSs on AD severity in 63 adult patients. METHODS: Disease severity was assessed with SCORAD index. The total immunoglobulin E (IgE) concentration was determined using the enzyme-linked immunosorbent assay method. The prevalence and abundance of staphylococci were assessed with the combination of bacterial culture and mass spectrometry. RESULTS: The prevalence values of SA within the skin (lesional/nonlesional) and anterior nares were 79.4%/61.9% and 69.8%, respectively (vs 5.6% and 13.9%, respectively in controls, P < 0.0001). The carriage of CNSs in all niches was associated with lower mean IgE concentration (1164.66 ± 1010.36 vs 1762.99 ± 1059.15, P < 0.0213; 1166.9 ± 1006.4 vs 2152.7 ± 759.2, P < 0.0063; 1022 ± 1100 vs 1925 ± 880.8, P < 0.0044, respectively). The abundance of SA correlated with the extent of skin lesions and total IgE (ρ = 0.42, P = 0.0007; ρ = 0.488, P < 0.0001; ρ = 0.312, P < 0.2; and ρ = 0.402, P = 0.0007; ρ = 0.403, P < 0.002; ρ = 0.287, P < 0.03, respectively). CONCLUSIONS: Atopic dermatitis severity correlates with both cutaneous and nasal colonization by SA. Staphylococcus aureus seems to promote TH2-type response, whereas CNS probably limits this process. Preventive measures within the anterior nares should be considered for AD patients.

Palmoplantar Pustulosis: Recent Advances in Etiopathogenesis and Emerging Treatments.

Palmoplantar pustulosis (PPP) is a chronic, recurrent skin disease belonging to the spectrum of psoriasis. It is characterized by an eruption of sterile pustules on the palms and soles. Recent studies in PPP have focused on genetic differences between pustular phenotypes and the role of the innate immunological system and the microbiome in the etiopathogenesis of the disease. Mutations in IL36RN (a major predisposing factor for generalized pustular psoriasis) were found in selected patients with PPP and were associated with earlier disease onset. Studies have shown that the interleukin (IL)-17 and IL-36 pathways might be involved in the pathogenesis of PPP. A microbiome has been demonstrated in the vesicopustules of PPP, and an abundance of Staphylococcus appears to be increased by smoking. Improved understanding of the underlying etiopathogenesis of PPP has led to advances in treatment options, and targeted therapies for PPP have been evaluated or are under evaluation against more than 12 molecules in ongoing clinical trials. These targets include CXCR2 (IL-8 receptor type B), granulocyte colony-stimulating factor receptor, IL-1 receptor, IL-8, IL-12, IL-23, IL-17A, IL-17 receptor, IL-36 receptor, phosphodiesterase-4, and tumor necrosis factor-α.

Claudin-1 decrease impacts epidermal barrier function in atopic dermatitis lesions dose-dependently.

The transmembrane protein claudin-1 is a major component of epidermal tight junctions (TJs), which create a dynamic paracellular barrier in the epidermis. Claudin-1 downregulation has been linked to atopic dermatitis (AD) pathogenesis but variable levels of claudin-1 have also been observed in healthy skin. To elucidate the impact of different levels of claudin-1 in healthy and diseased skin we determined claudin-1 levels in AD patients and controls and correlated them to TJ and skin barrier function. We observed a strikingly broad range of claudin-1 levels with stable TJ and overall skin barrier function in healthy and non-lesional skin. However, a significant decrease in TJ barrier function was detected in lesional AD skin where claudin-1 levels were further reduced. Investigations on reconstructed human epidermis expressing different levels of claudin-1 revealed that claudin-1 levels correlated with inside-out and outside-in barrier function, with a higher coherence for smaller molecular tracers. Claudin-1 decrease induced keratinocyte-autonomous IL-1ß expression and fostered inflammatory epidermal responses to non-pathogenic Staphylococci. In conclusion, claudin-1 decrease beyond a threshold level results in TJ and epidermal barrier function impairment and induces inflammation in human epidermis. Increasing claudin-1 levels might improve barrier function and decrease inflammation and therefore be a target for AD treatment.

The upper-airway microbiota and loss of asthma control among asthmatic children.

The airway microbiome has an important role in asthma pathophysiology. However, little is known on the relationships between the airway microbiome of asthmatic children, loss of asthma control, and severe exacerbations. Here we report that the microbiota's dynamic patterns and compositions are related to asthma exacerbations. We collected nasal blow samples (n = 319) longitudinally during a clinical trial at 2 time-points within one year: randomization when asthma is under control, and at time of early loss of asthma control (yellow zone (YZ)). We report that participants whose microbiota was dominated by the commensal Corynebacterium + Dolosigranulum cluster at RD experience the lowest rates of YZs (p = 0.005) and have longer time to develop at least 2 episodes of YZ (p = 0.03). The airway microbiota have changed from randomization to YZ. A switch from the Corynebacterium + Dolosigranulum cluster at randomization to the Moraxella- cluster at YZ poses the highest risk of severe asthma exacerbation (p = 0.04). Corynebacterium's relative abundance at YZ is inversely associated with severe exacerbation (p = 0.002).

A general approach for predicting protein epitopes targeted by antibody repertoires using whole proteomes.

Antibodies are essential to functional immunity, yet the epitopes targeted by antibody repertoires remain largely uncharacterized. To aid in characterization, we developed a generalizable strategy to predict antibody-binding epitopes within individual proteins and entire proteomes. Specifically, we selected antibody-binding peptides for 273 distinct sera out of a random library and identified the peptides using next-generation sequencing. To predict antibody-binding epitopes and the antigens from which these epitopes were derived, we tiled the sequences of candidate antigens into short overlapping subsequences of length k (k-mers). We used the enrichment over background of these k-mers in the antibody-binding peptide dataset to predict antibody-binding epitopes. As a positive control, we used this approach, termed K-mer Tiling of Protein Epitopes (K-TOPE), to predict epitopes targeted by monoclonal and polyclonal antibodies of well-characterized specificity, accurately recovering their known epitopes. K-TOPE characterized a commonly targeted antigen from Rhinovirus A, predicting four epitopes recognized by antibodies present in 87% of sera (n = 250). An analysis of 2,908 proteins from 400 viral taxa that infect humans predicted seven enterovirus epitopes and five Epstein-Barr virus epitopes recognized by >30% of specimens. Analysis of Staphylococcus and Streptococcus proteomes similarly predicted 22 epitopes recognized by >30% of specimens. Twelve of these common viral and bacterial epitopes agreed with previously mapped epitopes with p-values < 0.05. Additionally, we predicted 30 HSV2-specific epitopes that were 100% specific against HSV1 in novel and previously reported antigens. Experimentally validating these candidate epitopes could help identify diagnostic biomarkers, vaccine components, and therapeutic targets. The K-TOPE approach thus provides a powerful new tool to elucidate the organisms, antigens, and epitopes targeted by human antibody repertoires.

Medically important interactions of staphylococci with pathogenic fungi.

Staphylococci are common inhabitants at several human body sites and are also implicated in infections either as primary or opportunistic pathogens. These bacteria can thus both contribute to the host defense being a part of the commensalistic microbiota or synergize with the other microbes during the infection process. Among fungi, staphylococci interact synergistically with Candida spp. and Aspergillus fumigatus, and antagonistically with Cryptococcus neoformans and Trichosporon asahii. These interactions are highly dynamic and are orchestrated by a multitude of microbial and host factors. During such cross-talks, staphylococci can modulate the virulence, immune response or drug resistance of the coexisting microbe(s), thereby influencing the infection course, disease severity, treatment strategy and the clinical outcome.

Antineutrophil cytoplasmic antibodies and their relationship with disease activity and presence of staphylococcal superantigens in nasal swabs in patients having granulomatosis with polyangiitis: results of a study involving 115 patients from a single center.

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCAs) are considered a risk factor for granulomatosis with polyangiitis (GPA) exacerbation, especially when staphylococcal superantigens (SAgs) are present in nasal swabs. Their role in monitoring disease activity remains controversial. This study determined the relationship of ANCAs with disease activity and presence of SAgs in GPA patients. METHODS: Among a total of 115 GPA patients hospitalized in the period 2009-2016, we investigated the presence of SAgs and ANCA concentration. Blood samples and nasal swabs were taken at each visit (referred further to as episodes). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). RESULTS: We analyzed 362 episodes. ANCAs were detected in 215 (59.4%), while SAgs were detected in 126 (34.8%) episodes. We found a significant correlation between the presence of ANCAs and disease activity (p = 0.0032), as well as between their level and GPA severity (r = 0.25363, p = 0.000001). We also determined that an ANCA values ≥ 138 Ru/ml were an indicator of active disease with high specificity and low sensitivity (84.4% and 37.3%, respectively). The relationship between ANCA presence and the presence of SAgs was not confirmed; however, when SAgs were analyzed based on the different types, ANCA levels were found to be significantly higher in the group with SAg type B (p = 0.031). CONCLUSIONS: There was no detectable evidence for the association between ANCA level and the presence of SAgs. Although monitoring ANCA levels as a marker of disease activity may be clinically relevant, GPA management cannot proceed on the basis of ANCA levels alone. Key Points • ANCA concentration usually correlates with GPA activity, although in half of patients, ANCAs persist despite effective treatment and clinical remission. • ANCA values of 138 Ru/ml seem to be an indicator of active disease with high specificity, but low sensitivity. • Although there is a relevance for ANCA monitoring as a marker of disease activity, GPA management cannot be based on ANCA levels alone. • The suspected clinical correlation between ANCA formation and SAg presence in nasal swabs is not obvious and requires further investigations.

Staphylococcus pseudintermedius Sbi paralogs inhibit complement and bind IgM, IgG Fc and Fab.

The success of staphylococci as pathogens has been attributed, in part, to their ability to evade their hosts' immune systems. Although the proteins involved in evasion have been extensively studied in staphylococci affecting humans little characterization has been done with Staphylococcus pseudintermedius, an important cause of pyoderma in dogs. Staphylococcus aureus binder of immunoglobulin (Sbi) interferes with innate immune recognition by interacting with multiple host proteins. In this study, a S. pseudintermedius gene that shares 38% similarity to S. aureus Sbi was cloned from S. pseudintermedius strains representative of major clonal lineages bearing two paralogs of the protein. Binding of immunoglobulins and Fab and Fc fragments as well as interaction with complement was measured. S. pseudintermedius Sbi protein bound IgG from multiple species and canine complement C3, neutralized complement activity and bound to canine IgM and B cells. Evidence from this work suggests Sbi may play an important role in S. pseudintermedius immune evasion.

Staphylococcus succinus 14BME20 Prevents Allergic Airway Inflammation by Induction of Regulatory T Cells via Interleukin-10.

Asthma is a common chronic inflammatory disease, which is characterized by airway hyperresponsiveness (AHR), high serum levels of immunoglobulin (Ig)E, and recruitment of various inflammatory cells such as eosinophils and lymphocytes. Korean traditional fermented foods have been reported to exert beneficial effects against allergic diseases such as asthma and atopic dermatitis. In this study, we investigated whether Staphylococcus succinus strain 14BME20 (14BME20) isolated from doenjang, a traditional high-salt-fermented soybean food of Korea, exerts suppressive effects on allergic airway inflammation in a murine model. Mice were orally administered with 14BME20, then sensitized and challenged with ovalbumin as an allergen. Administration of the 14BME20 significantly suppressed AHR and influx of inflammatory cells into the lungs and reduced serum IgE levels. Moreover, the proportion of T helper type 2 (Th2) cells and the production of Th2 cytokines were decreased in 14BME20-treated mice, whereas dendritic cells (DCs) with tolerogenic characteristics were increased. In contrast, oral administration of 14BME20 increased the proportion of CD4+CD25+Foxp3+ regulatory T (Treg) cells and the level of interleukin (IL)-10 in 14BME20-treated mice. Furthermore, 14BME20 induced maturation of tolerogenic DCs, and 14BME20-treated DCs increased Treg cell population in a co-culture system of DCs and CD4+ T cells. The addition of a neutralizing anti-IL-10 mAb to the culture of cells that had been treated with 14BME20 decreased the enhanced Treg cell population, thereby indicating that 14BME20-treated DCs increase Treg cell population via DC-derived IL-10. These results demonstrate that oral administration of 14BME20 suppresses airway inflammation by enhancing Treg responses and suggest that the 14BME20 isolated from doenjang may be a therapeutic agent for allergic asthma.

The theory of a "staphylococcus superantigen" in chronic rhinosinusitis with nasal polyps: myth or reality?

OBJECTIVE: The aim of our study was to search for evidence of a "staphylococcus superantigen" in chronic rhinosinusitis with nasal polyps. PATIENTS AND METHODS: Sixty-nine patients with chronic rhinosinusitis with nasal polyps and 45 healthy controls were included in the study. All patients in the study and control groups underwent bacteriological and immunological examination on nasal smear samples. Total IgE and the following cytokines were tested in all patients: tumor necrosis factor (TNF), interleukin-1 (IL1), interleukin-6 (IL6), interleukin-8 (IL8). RESULTS: The concentration of bacteria in the nasal cavity was much higher in patients in the study group compared to those in the control group, mainly due to staphylococci. In species identification of staphylococci, bacteria most represented were S. aureus and S. epidermidis. The greater the concentration of S. aureus, the lower the level of IgE. Proinflammatory cytokines were uniformly increased in patients with nasal polyps. The level of IgE was maximal in patients with chronic rhinosinusitis with nasal polyps with a poor growth of culture and minimal in patients with abundant growth, suggesting that in the latter the effect of eosinophilic inflammation on the disease was reduced, and conversely, the activity of eosinophilic inflammation was maximal with a poor seeding of the nasal cavity. CONCLUSIONS: Although this study has some limits, our findings do not support the theory of a staphylococcus superantigen in which the IgE level and eosinophilic inflammation should increase with increasing activity of Staphylococcus aureus. Further research supported by a larger sample of patients is required to better delineate the role of a staphylococcus superantigen in the pathogenesis of patients with chronic rhinosinusitis with nasal polyps.