SLUSH peptides of the PSMβ family enable Staphylococcus lugdunensis to use erythrocytes as a sole source of nutrient iron.

During infection, the host employs nutritional immunity to restrict access to iron. Staphylococcus lugdunensis has been recognized for its ability to utilize host-derived heme to overcome iron restriction. However, the mechanism behind this process involves the release of hemoglobin from erythrocytes, and the hemolytic factors of S.

Antimicrobial Evaluation of Two Polycyclic Polyprenylated Acylphloroglucinol Compounds: PPAP23 and PPAP53.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties.

Lipase-mediated detoxification of host-derived antimicrobial fatty acids by Staphylococcus aureus.

Long-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such as Staphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used by S.

A type VII-secreted lipase toxin with reverse domain arrangement.

The type VII protein secretion system (T7SS) is found in many Gram-positive bacteria and in pathogenic mycobacteria. All T7SS substrate proteins described to date share a common helical domain architecture at the N-terminus that typically interacts with other helical partner proteins, forming a composite signal sequence for targeting to the T7SS. The C-terminal domains are functionally diverse and in Gram-positive bacteria such as Staphylococcus aureus often specify toxic anti-bacterial activity.

Wall Teichoic Acid Mediates Binding to Endothelial Cells via the Scavenger Receptor LOX-1.

The success of as a major cause for endovascular infections depends on effective interactions with blood-vessel walls. We have previously shown that uses its wall teichoic acid (WTA), a surface glycopolymer, to attach to endothelial cells. However, the endothelial WTA receptor remained unknown.

Keratinocytes use FPR2 to detect and initiate antimicrobial skin defense.

Introduction: Keratinocytes form a multilayer barrier that protects the skin from invaders or injuries. The barrier function of keratinocytes is in part mediated by the production of inflammatory modulators that promote immune responses and wound healing. Skin commensals and pathogens such as secrete high amounts of phenol-soluble modulin (PSM) peptides, agonists of formyl-peptide receptor 2 (FPR2).

The epidermal lipid barrier in microbiome-skin interaction.

The corneocyte layers forming the upper surface of mammalian skin are embedded in a lamellar-membrane matrix which repels harmful molecules while retaining solutes from subcutaneous tissues. Only certain bacterial and fungal taxa colonize skin surfaces. They have ways to use epidermal lipids as nutrients while resisting antimicrobial fatty acids.

Cytotoxicity Assays as Predictors of the Safety and Efficacy of Antimicrobial Agents.

The development of safe antimicrobial agents is important for the effective treatment of pathogens. From a multitude of discovered inhibitory compounds, only a few antimicrobial agents are able to enter the market. Many antimicrobials are, on the one hand, quite effective in killing pathogens but, on the other hand, cytotoxic to eukaryotic cells.

Short-Chain Fatty Acid and FFAR2 Activation - A New Option for Treating Infections?

The human innate immune system is equipped with multiple mechanisms to detect microbe-associated molecular patterns (MAMPs) to fight bacterial infections. The metabolite short-chain fatty acids (SCFAs) acetate, propionate and butyrate are released by multiple bacteria or are food ingredients. SCFA production, especially acetate production, is usually essential for bacteria, and knockout of pathways involved in acetate production strongly impairs bacterial fitness.

Bacterial membrane vesicles shape Staphylococcus aureus skin colonization and induction of innate immune responses.

Staphylococcus aureus colonization is abundant on the skin of atopic dermatitis (AD) patients where it contributes to skin inflammation. S. aureus produces virulence factors that distinguish it from commensal skin bacteria such as S.

Depends on Eap Proteins for Preventing Degradation of Its Phenol-Soluble Modulin Toxins by Neutrophil Serine Proteases.

Neutrophil granulocytes act as a first line of defense against pathogenic staphylococci. However, has a remarkable capacity to survive neutrophil killing, which distinguishes it from the less-pathogenic Both species release phenol-soluble modulin (PSM) toxins, which activate the neutrophil formyl-peptide receptor 2 (FPR2) to promote neutrophil influx and phagocytosis, and which disrupt neutrophils or their phagosomal membranes at high concentrations. We show here that the neutrophil serine proteases (NSPs) neutrophil elastase, cathepsin G and proteinase 3, which are released into the extracellular space or the phagosome upon neutrophil FPR2 stimulation, effectively degrade PSMs thereby preventing their capacity to activate and destroy neutrophils.

Acetate sensing by GPR43 alarms neutrophils and protects from severe sepsis.

Bacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection. Effective immunomodulatory approaches are urgently needed but it has remained elusive, which targets might be suitable for intervention. Increased expression of the G-protein-coupled receptor GPR43, which is known to govern intestinal responses to acetate, has been associated with sepsis patient survival but the mechanisms behind this observation have remained unclear.

Inhibition of the ATP synthase sensitizes Staphylococcus aureus towards human antimicrobial peptides.

Antimicrobial peptides (AMPs) are an important part of the human innate immune system for protection against bacterial infections, however the AMPs display varying degrees of activity against Staphylococcus aureus. Previously, we showed that inactivation of the ATP synthase sensitizes S. aureus towards the AMP antibiotic class of polymyxins.

Formyl-Peptide Receptor Activation Enhances Phagocytosis of Community-Acquired Methicillin-Resistant Staphylococcus aureus.

Background: Formyl-peptide receptors (FPRs) are important pattern recognition receptors that sense specific bacterial peptides. Formyl-peptide receptors are highly expressed on neutrophils and monocytes, and their activation promotes the migration of phagocytes to sites of infection. It is currently unknown whether FPRs may also influence subsequent processes such as bacterial phagocytosis and killing.

Staphylococcus aureus Lpl protein triggers human host cell invasion via activation of Hsp90 receptor.

Staphylococcus aureus is a facultative intracellular pathogen. Recently, it has been shown that the protein part of the lipoprotein-like lipoproteins (Lpls), encoded by the lpl cluster comprising of 10 lpls paralogue genes, increases pathogenicity, delays the G2/M phase transition, and also triggers host cell invasion. Here, we show that a recombinant Lpl1 protein without the lipid moiety binds directly to the isoforms of the human heat shock proteins Hsp90α and Hsp90ß.

The Mechanism behind Bacterial Lipoprotein Release: Phenol-Soluble Modulins Mediate Toll-Like Receptor 2 Activation via Extracellular Vesicle Release from Staphylococcus aureus.

The innate immune system uses Toll-like receptor (TLR) 2 to detect conserved bacterial lipoproteins of invading pathogens. The lipid anchor attaches lipoproteins to the cytoplasmic membrane and prevents their release from the bacterial cell envelope. How bacteria release lipoproteins and how these molecules reach TLR2 remain unknown.

Staphylococcal Enterotoxins Dose-Dependently Modulate the Generation of Myeloid-Derived Suppressor Cells.

is one of the major human bacterial pathogens causing a broad spectrum of serious infections. Myeloid-derived suppressor cells (MDSC) represent an innate immune cell subset capable of regulating host-pathogen interactions, yet their role in the pathogenesis of infections remains incompletely defined. The aim of this study was to determine the influence of different strains and associated virulence factors on human MDSC generation.

Formyl-Peptide Receptors in Infection, Inflammation, and Cancer.

Formyl-peptide receptors (FPRs) recognize bacterial and mitochondrial formylated peptides as well as endogenous non-formylated peptides and even lipids. FPRs are expressed on various host cell types but most strongly on neutrophils and macrophages. After the discovery of FPRs on leukocytes, it was assumed that these receptors predominantly govern a proinflammatory response resulting in chemotaxis, degranulation, and oxidative burst during infection.

Phenol-Soluble Modulin Peptides Contribute to Influenza A Virus-Associated Staphylococcus aureus Pneumonia.

Influenza A virus (IAV) infection is often followed by secondary bacterial lung infection, which is a major reason for severe, often fatal pneumonia. Community-associated methicillin-resistant (CA-MRSA) strains such as USA300 cause particularly severe and difficult-to-treat cases of IAV-associated pneumonia. CA-MRSA strains are known to produce extraordinarily large amounts of phenol-soluble modulin (PSM) peptides, which are important cytotoxins and proinflammatory molecules that contribute to several types of infection.

Formyl-peptide receptor 2 governs leukocyte influx in local infections.

Leukocytes express formyl-peptide receptors (FPRs), which sense microbe-associated molecular pattern (MAMP) molecules, leading to leukocyte chemotaxis and activation. We recently demonstrated that phenol-soluble modulin (PSM) peptides from highly pathogenic are efficient ligands for the human FPR2. How PSM detection by FPR2 impacts on the course of infections has remained unknown.

Wall teichoic acids mediate increased virulence in Staphylococcus aureus.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are the cause of a severe pandemic consisting primarily of skin and soft tissue infections. The underlying pathomechanisms have not been fully understood and we report here a mechanism that plays an important role for the elevated virulence of CA-MRSA. Surprisingly, skin abscess induction in an animal model was correlated with the amount of a major cell wall component of S.

Cytotoxicity Assays as Predictors of the Safety and Efficacy of Antimicrobial Agents.

The development of safe antimicrobial agents is important for the effective treatment of pathogens. From a multitude of discovered inhibitory compounds only few antimicrobial agents are able to enter the market. Many antimicrobials are, on the one hand, quite effective in killing pathogens but, on the other hand, cytotoxic to eukaryotic cells.

Lipoprotein immunoproteomics question the potential of Staphylococcus aureus TLR2 agonists as vaccine antigens.

Toll-like receptor 2 (TLR2) is regarded as the major innate immunity sensor in infections caused by the Gram-positive bacterial pathogen Staphylococcus aureus. However, previous studies on the roles of TLR2 in S. aureus infections have been elusive and in part contradictory.

Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes.

Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S.