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Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries (1). Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction (2). Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis (3). Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence (4). More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen (5). Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis (6). However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified δ-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by δ-toxin depended on phosphoinositide 3-kinase and calcium ([Ca.sup.2+]) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced δ-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S.aureusisolates recovered from patients with atopic dermatitis produced large amounts of δ-toxin. Skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by δ-toxin was abrogated in [Kit.sup.W-sh/W-sh] mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify δ-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureuscolonization and allergic skin disease., Because mast cells (MCs) may play a critical role in the pathogenesis of atopic dermatitis (3), we asked first whether S. aureus can release factors that induce MC degranulation. We [...]

Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus (1) calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection (2). Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis (3-5) and have a major impact on the ability of highly virulent S. aureus to cause disease (3), (6). However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here we report that an ATP-binding cassette transporter with previously unknown function is responsible for the export of all PSMs, thus representing a single target for complete obstruction of PSM production. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the extent of its effect on the development of S. aureus infection was similar to that of the sum of all PSMs. Notably, the transporter was essential for bacterial growth. Furthermore, it contributed to producer immunity toward secreted PSMs and defense against PSM-mediated bacterial interference. Our study reveals a noncanonical, dedicated secretion mechanism for an important class of toxins and identifies this mechanism as a comprehensive potential target for the development of drugs to efficiently inhibit the growth and virulence of pathogenic staphylococci., Several observations point to the value of targeting PSMs for drug development. First, PSMs have multiple crucial roles in pathogenesis. They efficiently lyse red and white blood cells (3), (7), [...]

The finding that protein A of Staphylococcus aureus diverts the immune response so that it ineffectively responds to other structures from the bacterium explains the failure of ongoing attempts to develop working S. aureus vaccines., ('Staphylococcus aureus is a global pathogen of great importance, causing thousands of deaths each year in the United States alone. The main problems with S. aureus infections are frequent resistance [...]

Comparative analysis between the DNA sequences of multiple fluorescent protein genes in terms of condons and GC content and a low-GC gram-positive bacterium, Bacillus anthracis is presented. The activity of the protective antigen promoter of B. anthracis is monitored by optimized GFP as a reporter to confirm its dependence on bicarbonate and regulators present on virulence plasmid pXO1.