SEC is an antiangiogenic virulence factor that promotes Staphylococcus aureus endocarditis independent of superantigen activity.

The superantigen staphylococcal enterotoxin C (SEC) is critical for Staphylococcus aureus infective endocarditis (SAIE) in rabbits. Superantigenicity, its hallmark function, was proposed to be a major underlying mechanism driving SAIE but was not directly tested. With the use of S. aureus MW2 expressing SEC toxoids, we show that superantigenicity does not sufficiently account for vegetation growth, myocardial inflammation, and acute kidney injury in the rabbit model of native valve SAIE. These results highlight the critical contribution of an alternative function of superantigens to SAIE. In support of this, we provide evidence that SEC exerts antiangiogenic effects by inhibiting branching microvessel formation in an ex vivo rabbit aortic ring model and by inhibiting endothelial cell expression of one of the most potent mediators of angiogenesis, VEGF-A. SEC's ability to interfere with tissue revascularization and remodeling after injury serves as a mechanism to promote SAIE and its life-threatening systemic pathologies.

Staphylococcus aureus ß-Toxin Exerts Anti-angiogenic Effects by Inhibiting Re-endothelialization and Neovessel Formation.

Staphylococcus aureus causes severe, life-threatening infections that often are complicated by severe local and systemic pathologies with non-healing lesions. A classic example is S. aureus infective endocarditis (IE), where the secreted hemolysin ß-toxin potentiates the disease via its sphingomyelinase and biofilm ligase activities. Although these activities dysregulate human aortic endothelial cell activation, ß-toxin effect on endothelial cell function in wound healing has not been addressed. With the use of the ex vivo rabbit aortic ring model, we provide evidence that ß-toxin prevents branching microvessel formation, highlighting its ability to interfere with tissue re-vascularization and vascular repair. We show that ß-toxin specifically targets both human aortic endothelial cell proliferation and cell migration and inhibits human umbilical vein endothelial cell rearrangement into capillary-like networks in vitro. Proteome arrays specific for angiogenesis-related molecules provided evidence that ß-toxin promotes an inhibitory profile in endothelial cell monolayers, specifically targeting production of TIMP-1, TIMP-4, and IGFBP-3 to counter the effect of a pro-angiogenic environment. Dysregulation in the production of these molecules is known to result in sprouting defects (including deficient cell proliferation, migration, and survival), vessel instability and/or vascular regression. When endothelial cells are grown under re-endothelialization/wound healing conditions, ß-toxin decreases the pro-angiogenic molecule MMP-8 and increases the anti-angiogenic molecule endostatin. Altogether, the data indicate that ß-toxin is an anti-angiogenic virulence factor and highlight a mechanism where ß-toxin exacerbates S. aureus invasive infections by interfering with tissue re-vascularization and vascular repair.

Laryngotracheal Microbiota in Adult Laryngotracheal Stenosis.

Laryngotracheal stenosis is an obstructive respiratory disease that leads to voicing difficulties and dyspnea with potential life-threatening consequences. The majority of incidences are due to iatrogenic etiology from endotracheal tube intubation; however, airway scarring also has idiopathic causes. While recent evidence suggests a microbial contribution to mucosal inflammation, the microbiota associated with different types of stenosis has not been characterized. High-throughput sequencing of the V4 region of the16S rRNA gene was performed to characterize the microbial communities of 61 swab samples from 17 iatrogenic and 10 adult idiopathic stenosis patients. Nonscar swabs from stenosis patients were internal controls, and eight swabs from four patients without stenosis represented external controls. Significant differences in diversity were observed between scar and nonscar samples and among sample sites, with decreased diversity detected in scar samples and the glottis region. Permutational analysis of variance (PERMANOVA) results revealed significant differences in community composition for scar versus nonscar samples, etiology type, sample site, groups (iatrogenic, idiopathic, and internal and external controls), and individual patients. Pairwise Spearman's correlation revealed a strong inverse correlation between Prevotella and Streptococcus among all samples. Finally, bacteria in the family Moraxellaceae were found to be distinctly associated with idiopathic stenosis samples in comparison with external controls. Our findings suggest that specific microbiota and community shifts are present with laryngotracheal stenosis in adults, with members of the family Moraxellaceae, including the known pathogens Moraxella and Acinetobacter, identified in idiopathic scar. Further work is warranted to elucidate the contributing role of bacteria on the pathogenesis of laryngotracheal stenosis.IMPORTANCE The laryngotracheal region resides at the intersection between the heavily studied nasal cavity and lungs; however, examination of the microbiome in chronic inflammatory conditions of the subglottis and trachea remains scarce. To date, studies have focused on the microbiota of the vocal folds, or the glottis, for laryngeal carcinoma, as well as healthy larynges, benign vocal fold lesions, and larynges exposed to smoking and refluxate. In this study, we seek to examine the structure and composition of the microbial community in adult laryngotracheal stenosis of various etiologies. Due to the heterogeneity among the underlying pathogenesis mechanisms and clinical outcomes seen in laryngotracheal stenosis disease, we hypothesized that different microbial profiles will be detected among various stenosis etiology types. Understanding differences in the microbiota for subglottic stenosis subtypes may shed light upon etiology-specific biomarker identification and offer novel insights into management approaches for this debilitating disease.

Insights Into the Role of Collagen in Vocal Fold Health and Disease.

As one of the key fibrous proteins in the extracellular matrix, collagen plays a significant role in the structural and biomechanical characteristics of the vocal fold. Anchored fibrils of collagen create secure structural regions within the vocal folds and are strong enough to sustain vibratory impact and stretch during phonation. This contributes tensile strength, density, and organization to the vocal folds and influences health and pathogenesis. This review offers a comprehensive summary for a current understanding of collagen within normal vocal fold tissues throughout the life span as well as vocal pathology and wound repair. Further, collagen's molecular structure and biosynthesis are discussed. Finally, collagen alterations in tissue injury and repair and the incorporation of collagen-based biomaterials as a method of treating voice disorders are reviewed.

Timing of Voice Therapy: A Primary Investigation of Voice Outcomes for Surgical Benign Vocal Fold Lesion Patients.

OBJECTIVE: This study aims to examine the role of timing of speech-language pathology intervention on outcomes for surgical patients with benign vocal fold lesions as measured by a patient self-reported scale (Voice Handicap Index [VHI]) and objective acoustic measures (jitter %, Dysphonia Severity Index, noise-to-harmonics ratio). For the purpose of this study, interventions were categorized into three groups: preoperative (preoperative counseling session followed by postoperative therapy), pre- and postoperative therapy (multiple therapy sessions preoperatively and postoperatively), and postoperative therapy alone. STUDY DESIGN: Retrospective review of a prospective disease-specific outcomes database. METHODS: Subjects identified in the database consisted of 12 preoperative counseling participants (six male, six female), 11 pre- and postoperative therapy participants (three male, eight female), and eight postoperative therapy only participants (three male, five female). Preoperative and postoperative VHI, Dysphonia Severity Index, jitter, and noise-to-harmonics ratio scores were compared between groups using paired t tests with a multiple comparison Bonferroni correction (α = 0.016). RESULTS: Despite lack of statistically significant changes in acoustic measures, groups receiving preoperative intervention whether with postoperative therapy or not, had statistically significant improvements in their VHI total scores (P = 0.001 for preoperative only and P = 0.0002 for pre- and postoperative therapy). CONCLUSIONS: Patients receiving speech pathology services before surgery for benign vocal fold lesions with or without postoperative therapy demonstrated greater gains in their subjective view of vocal function and quality as measured by the VHI.