Epidermal clearance of Candida albicans is mediated by IL-17 but independent of fungal innate immune receptors.

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.

Application of an agr-Specific Antivirulence Compound as Therapy for Staphylococcus aureus-Induced Inflammatory Skin Disease.

Atopic dermatitis (AD) is a chronic inflammatory skin disease where more than 90% of patients affected are colonized with Staphylococcus aureus. In AD, S. aureus δ-toxin is a major virulence factor causing cutaneous inflammation via mast cell degranulation. δ-toxin is controlled by the S. aureus agr quorum sensing system, and thus we addressed whether interference with agr signaling would limit skin inflammation. Indeed, treatment of S. aureus with the agr-inhibitor solonamide B (SolB) abolished δ-toxin production and reduced skin inflammation in a mouse model of inflammatory skin disease, demonstrating the potential of antivirulence therapy in treating S. aureus-induced skin disorders.

The role of Staphylococcus aureus quorum sensing in cutaneous and systemic infections.

BACKGROUND: Staphylococcus aureus is a leading cause of human bacterial infections worldwide. It is the most common causative agent of skin and soft tissue infections, and can also cause various other infections, including pneumonia, osteomyelitis, as well as life-threatening infections, such as sepsis and infective endocarditis. The pathogen can also asymptomatically colonize human skin, nasal cavity, and the intestine. S. aureus colonizes approximately 20-30% of human nostrils, being an opportunistic pathogen for subsequent infection. Its strong ability to silently spread via human contact makes it difficult to eradicate S. aureus. A major concern with S. aureus is its capacity to develop antibiotic resistance and adapt to diverse environmental conditions. The variability in the accessory gene regulator (Agr) region of the genome contributes to a spectrum of phenotypes within the bacterial population, enhancing the likelihood of survival in different environments. Agr functions as a central quorum sensing (QS) system in S. aureus, allowing bacteria to adjust gene expression in response to population density. Depending on Agr expression, S. aureus secretes various toxins, contributing to virulence in infectious diseases. Paradoxically, expressing Agr may be disadvantageous in certain situations, such as in hospitals, causing S. aureus to generate Agr mutants responsible for infections in healthcare settings. MAIN BODY: This review aims to demonstrate the molecular mechanisms governing the diverse phenotypes of S. aureus, ranging from a harmless colonizer to an organism capable of infecting various human organs. Emphasis will be placed on QS and its role in orchestrating S. aureus behavior across different contexts. SHORT CONCLUSION: The pathophysiology of S. aureus infection is substantially influenced by phenotypic changes resulting from factors beyond Agr. Future studies are expected to give the comprehensive understanding of S. aureus overall profile in various settings.

Amputation-free Home Management of Infected Lower Extremity Pressure Ulcer through Shared Decision-making: Enhancing the Quality of Life and Highlighting Societal Significance in Home Care.

Home healthcare is important for allowing patients to live their lives. However, home-care bedridden patients often experience pressure ulcers in the lower extremities, which can lead to life-threatening infections requiring decisions on the need for amputation. We herein report a patient with an infected lower-limb pressure ulcer with a history of spinal injury. The patient, his family, and the home-care physician repeatedly shared decision-making to deliver home-based treatment instead of amputation. Administration of wound dressing, AQUACEL® Ag, led to complete epithelialization. Such shared decision-making and dressing were feasible in a home-care setting and broadened its scope.

Pathogenic role of the staphylococcal accessory gene regulator quorum sensing system in atopic dermatitis.

The skin is home to various bacteria, archaea, fungi, and viruses, collectively referred to as the skin microbiota. Patients with certain skin diseases reportedly have unique skin "dysbiosis," a condition involving imbalanced microbiota, suggesting that dysbiosis in the skin may be either causal or a consequence of specific skin diseases. Atopic dermatitis (AD) is the most common allergic skin disease that affects 15-20% of children and 2-10% of adults worldwide. Both intrinsic genetic factors, such as susceptibility to type 2 inflammation or skin barrier dysfunction, and extrinsic environmental factors, such as air pollen and skin microbiota, contribute to AD. Staphylococcus aureus, which does not often colonize the skin of healthy individuals, is commonly identified in the lesional skin of patients with AD and is correlated with the disease flare. However, the role of S. aureus in the pathogenesis of AD has not been elucidated. Here, we discuss the pathological behavior of S. aureus, focusing on accessory gene regulator (Agr) quorum sensing, which is a fundamental bacterial cell-to-cell interaction mechanism that affects the behavior of S. aureus and other members of the microbial community. Importantly, beyond bacteria-bacteria interactions, the Agr quorum sensing system also regulates various virulence factors, which induce type 2 and IL-17-dependent skin inflammation in the host. Furthermore, the colonization of Agr-positive S. aureus in early life accelerates the development of pediatric AD. Finally, we aim to highlight the current efforts to establish novel therapeutic methods to ameliorate or prevent AD through Agr-targeted intervention.

Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury.

Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single cell RNA-sequencing, we uncovered both direct and indirect paths by which these resident SG progenitors ordinarily differentiate into sebocytes, including transit through a PPARγ+Krt5+ transitional cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.

Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury.

Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single-cell RNA sequencing, we uncovered both direct and indirect paths by which resident SG progenitors ordinarily differentiate into sebocytes, including transit through a Krt5+PPARγ+ transitional basal cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair-follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR2 signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.

Interaction between Staphylococcus Agr virulence and neutrophils regulates pathogen expansion in the skin.

Staphylococcus aureus commonly infects the skin, but the host-pathogen interactions controlling bacterial growth remain unclear. S. aureus virulence is regulated by the Agr quorum-sensing system that controls factors including phenol-soluble modulins (PSMs), a group of cytotoxic peptides. We found a differential requirement for Agr and PSMα for pathogen growth in the skin. In neutrophil-deficient mice, S. aureus growth on the epidermis was unaffected, but the pathogen penetrated the dermis through mechanisms that require PSMα. In the dermis, pathogen expansion required Agr in wild-type mice, but not in neutrophil-deficient mice. Agr limited oxidative and non-oxidative killing in neutrophils by inhibiting pathogen late endosome localization and promoting phagosome escape. Unlike Agr, the SaeR/S virulence program was dispensable for growth in the epidermis and promoted dermal pathogen expansion independently of neutrophils. Thus, S. aureus growth and invasion are differentially regulated with Agr limiting intracellular killing within neutrophils to promote pathogen expansion in the dermis and subcutaneous tissue.

Rosmarinus officinalis L. (Rosemary) Extracts Containing Carnosic Acid and Carnosol are Potent Quorum Sensing Inhibitors of Staphylococcus aureus Virulence.

Staphylococcus aureus is an opportunistic pathogen and a common cause of skin infection. S. aureus also plays a role in the pathogenesis of the chronic inflammatory skin disease, atopic dermatitis. S. aureus virulence involves activation of the quorum sensing agr operon. In this paper, we show that the diterpene carnosic acid, present in R. officinalis L. (rosemary) leaves, is a specific inhibitor of S. aureus agr expression as low as 5 µM. Carnosol and rosmarinic acid are two other phytochemicals present in rosemary leaves. Carnosol, but not rosmarinic acid, is also a potent agr expression inhibitor. Natural rosemary extracts containing carnosic acid and carnosol inhibit S. aureus agr expression, both in luciferase reporter strains and in wild type strains isolated from patients with atopic dermatitis. Specific inhibition of S. aureus virulence using topical formulations of rosemary extract may offer a practical approach to preventing and treating flares of atopic dermatitis.

Staphylococcus Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development.

Atopic dermatitis (AD) is commonly associated with colonization by Staphylococcus aureus in the affected skin. To understand the role of S. aureus in the development of AD, we performed whole-genome sequencing of S. aureus strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with S. aureus at 1 month regardless of AD outcome. In contrast, skin colonization by S. aureus at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the S. aureus Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in S. aureus was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional S. aureus agr virulence during infancy is associated with pathogen skin colonization and the development of AD.

Streptococcal Cysteine Protease-Mediated Cleavage of Desmogleins Is Involved in the Pathogenesis of Cutaneous Infection.

Streptococcus pyogenes is responsible for a wide variety of cutaneous infections ranging from superficial impetigo to fulminant invasive necrotizing fasciitis. Dysfunction of desmosomes is associated with the pathogenesis of cutaneous diseases. We identified streptococcal pyrogenic exotoxin B (SpeB) as a proteolytic factor that cleaves the extracellular domains of desmoglein 1 and 3. In an epicutaneous infection model, lesional skin infected with an speB deletion mutant were significantly smaller as compared to those caused by the wild-type strain. Furthermore, immunohistological analysis indicated cleavage of desmogleins that developed around the invasion site of the wild-type strain. In contrast, the speB mutant was preferentially found on the epidermis surface layer. Taken together, our findings provide evidence that SpeB-mediated degradation of desmosomes has a pathogenic role in development of S. pyogenes cutaneous infection.

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation.

Staphylococcus aureus commonly colonizes the epidermis, but the mechanisms by which the host senses virulent, but not commensal, S. aureus to trigger inflammation remain unclear. Using a murine epicutaneous infection model, we found that S. aureus-expressed phenol-soluble modulin (PSM)α, a group of secreted virulence peptides, is required to trigger cutaneous inflammation. PSMα induces the release of keratinocyte IL-1α and IL-36α, and signaling via IL-1R and IL-36R was required for induction of the pro-inflammatory cytokine IL-17. The levels of released IL-1α and IL-36α, as well as IL-17 production by γδ T cells and ILC3 and neutrophil infiltration to the site of infection, were greatly reduced in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88. Further, Il17a-/-f-/- mice showed blunted S. aureus-induced inflammation. Thus, keratinocyte Myd88 signaling in response to S. aureus PSMα drives an IL-17-mediated skin inflammatory response to epicutaneous S. aureus infection.