Staphylococcus aureus is a formidable human pathogen responsible for infections ranging from superficial skin lesions to life-threatening systemic diseases. This review synthesizes current knowledge on its pathogenesis, emphasizing colonization dynamics, virulence mechanisms, biofilm formation, and antibiotic resistance. By analyzing studies from PubMed, Scopus, and Web of Science, we highlight the pathogen's adaptability, driven by surface adhesins (e.g., ClfB, SasG), secreted toxins (e.g., PVL, TSST-1), and metabolic flexibility in iron acquisition and amino acid utilization. Nasal, skin, and oropharyngeal colonization are reservoirs for invasive infections, with biofilm persistence and horizontal gene transfer exacerbating antimicrobial resistance, particularly in methicillin-resistant S. aureus (MRSA). The review underscores the clinical challenges of multidrug-resistant strains, including vancomycin resistance and decolonization strategies' failure to target single anatomical sites. Key discussions address host-microbiome interactions, immune evasion tactics, and the limitations of current therapies. Future directions advocate for novel anti-virulence therapies, multi-epitope vaccines, and AI-driven diagnostics to combat evolving resistance. Strengthening global surveillance and interdisciplinary collaboration is critical to mitigating the public health burden of S. aureus.

Germline signal transducer and activator of transcription 3 (STAT3) mutations cause 2 distinct syndromes with predominant infectious or autoimmune phenotype.

The objective of this study is to compile literature reports on gain-of-function (GOF) and dominant-negative (DN) mutations in the STAT3.

We searched 3 main databases including PubMed, Scopus, and Web of Science from 1990 to 2023. All full-text articles and major reviews were manually searched for additional studies.

A total of 490 patients were reported in 107 articles including 265 patients with DN-STAT3 and 225 patients with GOF-STAT3 mutations. Major clinical differences between STAT3-DN and STAT3-GOF patients were observed in rates of infectious complication (98.2% vs 85.4%, P < .001), pneumonia (67.3% vs 52.1%, P = .006), sinusitis (17.5% vs 2.1%, P < .001), otitis (27.7% vs 5.2%, P < .001), abscess (52.7% vs 17.7%, P < .001), dermatologic manifestation (88.3% vs 58.4%, P < .001), atopic disorders (66.4% vs 40.2%, P < .001), interstitial lung disease (0.7% vs 17.7%, P < .001), dental/gingival disorders (38.5% vs 11.7%, P < .001), and endocrinopathies (0.9% vs 16.5%, P < .001), respectively. Most patients had normal counts of lymphocyte subsets, with the exceptions of higher CD3+ T cells and lower natural killer cells in STAT3-DN patients, and lower CD4+ T cells in STAT3-GOF patients. Most STAT3-DN patients had either normal or high serum concentrations of IgG, IgA, and IgM with almost universal raised serum IgE. Most STAT3-GOF patients had a low level of IgG, but normal levels of IgA, IgM, and IgE.

Patients with STAT3-DN had recurrent dermatological and pulmonary infections, eczema, elevated IgE, and eosinophilia, whereas patients with STAT3-GOF had early-onset polyautoimmunity and frequently require immunosuppressive therapy.

Staphylococcus aureus bacteremia (SAB) is a prevalent life-threatening infection often caused by methicillin-resistant S. aureus (MRSA). Up to 30% of SAB patients fail to clear infection even with gold-standard anti-MRSA antibiotics. This phenomenon is termed antibiotic-persistent MRSA bacteremia (APMB). The mechanisms driving APMB are complex and involve host phenotypes significantly impacting the immune response. Thus, defining early immune signatures and clinical phenotypes that differentiate APMB from antibiotic resolving (AR)MB could aid therapeutic success.

We assessed 38 circulating cytokines and chemokines using affinity proteomics in 74 matched pairs of vancomycin-treated SAB cases identified as ARMB or APMB after 5 days of blood culture.

Unsupervised hierarchical clustering segregated APMB from ARMB based on differential levels of IL-10, IL-12p40, IL-13, CCL4, and TGFα. Additionally, CXCL1, CCL22 and IL-17A significantly differed between APMB and ARMB when correlated with diabetes, dialysis, metastatic infection, or cardiac vegetation. Combining immune signatures with these relevant clinical phenotypes sharply increased accuracy of discriminating APMB outcome to 79.1% via logistic regression modeling. Finally, classification-regression tree analysis revealed explicit analyte thresholds associated with APMB outcome at presentation especially in patients with metastatic infection.

Collectively, this study identifies previously unrecognized cytokine and chemokine signatures that distinguish APMB and ARMB at presentation and in the context of host clinical characteristics associated with increased disease severity. Validation of a biomarker signature that accurately predicts outcomes could guide early therapeutic strategies and interventions to reduce risks of persistent SAB that are associated with worsened morbidity and mortality.

Staphylococcus aureus (S. aureus) is a Gram-positive bacterium of significant clinical importance, known for its versatility and ability to cause a wide array of infections, such as osteoarticular, pulmonary, cardiovascular, device-related, and hospital-acquired infections. This review describes the most recent evidence of the pathogenic potential of S. aureus, which is commonly part of the human microbiota but can lead to severe infections. The prevalence of pathogenic S. aureus in hospital and community settings contributes to substantial morbidity and mortality, particularly in individuals with compromised immune systems. The immunopathogenesis of S. aureus infections involves intricate interactions with the host immune and non-immune cells, characterized by various virulence factors that facilitate adherence, invasion, and evasion of the host's defenses. This review highlights the complexity of S. aureus infections, ranging from mild to life-threatening conditions, and underscores the growing public health concern posed by multidrug-resistant strains, including methicillin-resistant S. aureus (MRSA). This article aims to provide an updated perspective on S. aureus-related infections, highlighting the main diseases linked to this pathogen, how the different cell types, virulence factors, and signaling molecules are involved in the immunopathogenesis, and the future perspectives to overcome the current challenges to treat the affected individuals.

Staphylococcus aureus poses an enormous burden of morbidity and mortality worldwide. Making an efficacious vaccine has however proven extremely challenging. Due to colonizing interactions, pre-existing S. aureus-specific CD4+ T cells are often found in the human population and yet a detailed characterization of their phenotypes and how they might in turn impact vaccine efficacy are thus far unknown. Using an activation induced marker assay to sort for S. aureus-specific CD4+ T cells in an effector function-independent manner, single cell transcriptomic analysis was conducted. Remarkably, S. aureus-specific CD4+ T cells consisted not only of a broader spectrum of conventional T cells (Tcon) than previously described but also of regulatory T cells (Treg). As compared to polyclonally-activated CD4+ T cells, S. aureus-specific Tcon were enriched for the expression of the Th17-type cytokine genes IL17A, IL22 and IL26, while higher percentages of S. aureus-specific Treg expressed the T Cell Immunoreceptor with Ig and ITIM domains (TIGIT), a pleiotropic immune checkpoint. Notably, the antagonistic anti-TIGIT mAb Tiragolumab increased IL-1β production in response to S. aureus in vitro. Therefore, these results uncover the presence of S. aureus-specific TIGIT+ Treg in the blood of healthy subjects that could blunt responses to vaccination and indicate TIGIT as a potential targetable biomarker to overcome pre-exposure-induced immunosuppression.

Pathobionts have evolved many strategies to coexist with the host, but how immune evasion mechanisms contribute to the difficulty of developing vaccines against pathobionts is unclear. Meanwhile, Staphylococcus aureus (SA) has resisted human vaccine development to date. Here we show that prior SA exposure induces non-protective CD4+ T cell imprints, leading to the blunting of protective IsdB vaccine responses. Mechanistically, these SA-experienced CD4+ T cells express IL-10, which is further amplified by vaccination and impedes vaccine protection by binding with IL-10Rα on CD4+ T cell and inhibit IL-17A production. IL-10 also mediates cross-suppression of IsdB and sdrE multi-antigen vaccine. By contrast, the inefficiency of SA IsdB, IsdA and MntC vaccines can be overcome by co-treatment with adjuvants that promote IL-17A and IFN-γ responses. We thus propose that IL-10 secreting, SA-experienced CD4+ T cell imprints represent a staphylococcal immune escaping mechanism that needs to be taken into consideration for future vaccine development.

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.

The neuroimmune axis has been the focus of many studies, with special emphasis on the interactions between the central nervous system and the different immune cell subsets. T cells are namely recognized to play a critical role due to their interaction with nerves, by secreting cytokines and neurotrophins, which regulate the development, function, and survival of neurons. In this context, γδ T cells are particularly relevant, as they colonize specific tissues, namely the meninges, and have a wide variety of complex functions that balance physiological systems. Notably, γδ T cells are not only key components for maintaining brain homeostasis but are also responsible for triggering or preventing inflammatory responses in various pathologies, including neurodegenerative diseases as well as neuropsychiatric and developmental disorders. Here, we provide an overview of the current state of the art on the contribution of γδ T cells in neuropathophysiology and delve into the molecular mechanisms behind it. We aim to shed light on γδ T cell functions in the central nervous system while highlighting upcoming challenges in the field and providing new clues for potential therapeutic strategies.

Rheumatoid arthritis (RA) is an autoimmune condition that mostly impacts the joints. During the advanced phases of the disorder, it may be accompanied by other problems. While the precise cause of RA is uncertain, various research has been conducted to gain a better understanding of the immunological processes involved in the development of RA. T cells are acknowledged as significant contributors to the progression of RA because of their roles in cytokine secretion, antigen presentation, and facilitating B cells in the manufacture of antibodies. γδ T cells are a small subset of T cells that have significant functions in the context of infection and diseases linked with tumors. γδ T cells have been the subject of investigation in autoimmune disorders in recent years. This review focused on the involvement of γδ T lymphocytes in the development of RA. In this article, we provide an analysis of the immunological capabilities of γδ T cells, intending to comprehend their significance in RA, which could be pivotal in the creation of innovative clinical treatments.

Staphylococcus aureus is a Gram-positive bacterium that most frequently acquires antibiotic resistance. As an opportunistic pathogen, it can cause conditions such as bacteremia, sepsis, and myocarditis. Due to the social need for a vaccine against methicillin-resistant Staphylococcus aureus (MRSA), many research groups have been designing and studying vaccines for decades. In this study, we developed a multivalent vaccine and evaluated its efficacy by applying a novel adjuvant, β-glucan.

A vaccine composed of four pore-forming toxins from S. aureus was administered to rabbits 3 times, after which they were challenged with S. aureus USA 300 LAC strain. We measured changes in the rabbits' body weight to monitor systemic adverse reactions and analyzed the total immunoglobulin G antibody titer against the four antigens using enzyme-linked immunosorbent assay. For each rabbit, the number of abscesses and colony-forming units (CFU) in the kidneys were measured.

In all vaccinated groups, strong antibody responses against the four antigens were observed. After challenging with MRSA, the vaccinated groups showed less weight change compared to the non-vaccinated groups (average 5.7% versus 13.5%). Additionally, the number of renal abscesses was significantly lower in the vaccinated groups, with three individuals in group 1 (four antigens adjuvanted with β-glucan_PK1) showing no abscess formation. The number of bacteria identified in the kidneys was also statistically significantly lower in the vaccinated group compared to the non-vaccinated group.

We demonstrated that the four toxoid antigens we selected can protect against S. aureus infection in a rabbit model and that β-glucan could be used as an immune enhancer. Overall, our study shows that new antigen combinations can induce protective immunity in animal models and that a toxin-based vaccine can help control bacterial colonization.

Interleukin (IL) 17 is a proinflammatory cytokine belonging to a structurally related group of cytokines known as the IL-17 family. It has been profoundly studied for its contribution to the pathology of autoimmune diseases. However, it also plays an important role in homeostasis and the defense against extracellular bacteria and fungi. IL-17 is important for epithelial barriers, including the skin, where some of its cellular targets reside. Most of the research work on IL-17 has focused on its effects in the skin within the context of autoimmune diseases or sterile inflammation, despite also having impact on other skin conditions. In recent years, studies on the role of IL-17 in the defense against skin pathogens and in the maintenance of skin homeostasis mediated by the microbiota have grown in importance. Here we review and discuss the cumulative evidence regarding the main contribution of IL-17 in the maintenance of skin integrity as well as its protective or pathogenic effects during some skin infections.

Developing an effective Staphylococcus aureus (S. aureus) vaccine has been a challenging endeavor, as demonstrated by numerous failed clinical trials over the years. In this study, we formulated a vaccine containing a highly conserved moonlighting protein, the pyruvate dehydrogenase complex E2 subunit (PDHC), and showed that it induced strong protective immunity against epidemiologically relevant staphylococcal strains in various murine disease models. While antibody responses contributed to bacterial control, they were not essential for protective immunity in the bloodstream infection model. Conversely, vaccine-induced systemic immunity relied on γδ T cells. It has been suggested that prior S. aureus exposure may contribute to the reduction of vaccine efficacy. However, PDHC-induced protective immunity still facilitated bacterial clearance in mice previously exposed to S. aureus. Collectively, our findings indicate that PDHC is a promising serotype-independent vaccine candidate effective against both methicillin-sensitive and methicillin-resistant S. aureus isolates.

The Staphylococcus sp. are a dominant part of the human skin microbiome and present across the body. Staphylococcus epidermidis is a ubiquitous skin commensal, while S. aureus is thought to colonize at least 30% of the population. S. aureus are not only colonizers but a leading cause of skin and soft tissue infections and a critical healthcare concern. To understand how healthy human skin may differentiate commensal bacteria, such as S. epidermidis, from the potential pathogen methicillin-resistant S. aureus (MRSA), we use ex vivo human skin models that allow us to study this host-bacterial interaction in the most clinically relevant environment. Our work highlights the role of the outer stratum corneum as a protective physical barrier against invasion by colonizing Staphylococci. We show how the structural cells of the skin can internalize and respond to different Staphylococci with increasing sensitivity. In intact human skin, a discriminatory IL-1β response was identified, while disruption of the protective stratum corneum triggered an increased and more diverse immune response. We identified and localized tissue resident Langerhans cells (LCs) as a potential source of IL-1β and go on to show a dose-dependent response of MUTZ-LCs to S. aureus but not S. epidermidis. This suggests an important role of LCs in sensing and discriminating between bacteria in healthy human skin, particularly in intact skin and provides a detailed snapshot of how human skin differentiates between friend and potential foe. With the rise in antibiotic resistance, understanding the innate immune response of healthy skin may help us find ways to enhance or manipulate these natural defenses to prevent invasive infection.

Staphylococcus aureus (S. aureus) colonizes humans asymptomatically but can also cause opportunistic infections, ranging from mild skin infections to severe life-threatening conditions. Resistance and tolerance are two ways a host can survive an infection. Resistance is limiting the pathogen burden, while tolerance is limiting the health impact of a given pathogen burden. In previous work, we established that collaborative cross (CC) mouse line CC061 is highly susceptible to Methicillin-resistant S. aureus infection (MRSA, USA300), while CC024 is tolerant. To identify host genes involved in tolerance after S. aureus infection, we crossed CC061 mice and CC024 mice to generate F1 and F2 populations. Survival after MRSA infection in the F1 and F2 generations was 65% and 55% and followed a complex dominant inheritance pattern for the CC024 increased survival phenotype. Colonization in F2 animals was more extreme than in their parents, suggesting successful segregation of genetic factors. We identified a Quantitative Trait Locus (QTL) peak on chromosome 7 for survival and weight change after infection. In this QTL, the WSB/EiJ (WSB) allele was present in CC024 mice and contributed to their MRSA tolerant phenotype. Two genes, C5ar1 and C5ar2, have high-impact variants in this region. C5ar1 and C5ar2 are receptors for the complement factor C5a, an anaphylatoxin that can trigger a massive immune response by binding to these receptors. We hypothesize that C5a may have altered binding to variant receptors in CC024 mice, reducing damage caused by the cytokine storm and resulting in the ability to tolerate a higher pathogen burden and longer survival.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including Staphylococcus epidermidis (S. epidermidis).

To assess whether S. epidermidis antigens play a role in AD, we screened for candidate allergens and studied the T cell and humoral immune response against the extracellular serine protease (Esp).

To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to S. epidermidis extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry.

We identified Esp as the dominant candidate allergen of S. epidermidis. Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T cells reacting to Esp were detectable in both AD patients and healthy controls. The T cell response in healthy adults was characterized by IL-17, IL-22, IFN-γ, and IL-10, whereas the AD patients' T cells lacked IL-17 production and released only low amounts of IL-22, IFN-γ, and IL-10. In contrast, Th2 cytokine release was higher in T cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33.

The extracellular serine protease Esp of S. epidermidis can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T cell response in AD patients. This suggests that S. epidermidis can aggravate AD through the allergenic properties of Esp.

The skin is the most common site of Staphylococcus aureus infection, which can lead to various diseases, including invasive and life-threatening infections, through evasion of host defense. However, little is known about the host factors that facilitate the innate immune evasion of S. aureus in the skin. Chemerin, which is abundantly expressed in the skin and can be activated by proteases derived from S. aureus, has both direct bacteria-killing activity and immunomodulatory effects via interactions with its receptor CMKLR1. Here, we demonstrate that a lack of the chemerin/CMKLR1 axis increases the neutrophil-mediated host defense against S. aureus in a mouse model of cutaneous infection, whereas chemerin overexpression, which mimics high levels of chemerin in obese individuals, exacerbates S. aureus cutaneous infection. Mechanistically, we identified keratinocytes that express CMKLR1 as the main target of chemerin to suppress S. aureus-induced IL-33 expression, leading to impaired skin neutrophilia and bacterial clearance. CMKLR1 signaling specifically inhibits IL-33 expression induced by cell wall components but not secreted proteins of S. aureus by inhibiting Akt activation in mouse keratinocytes. Thus, our study revealed that the immunomodulatory effect of the chemerin/CMKLR1 axis mediates innate immune evasion of S. aureus in vivo and likely increases susceptibility to S. aureus infection in obese individuals.

γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.

IL-1, a pleiotropic cytokine with profound effects on various cell types, particularly immune cells, plays a pivotal role in immune responses. The proinflammatory nature of IL-1 necessitates stringent control mechanisms of IL-1-mediated signaling at multiple levels, encompassing transcriptional and translational regulation, precursor processing, as well as the involvement of a receptor accessory protein, a decoy receptor, and a receptor antagonist. In T-cell immunity, IL-1 signaling is crucial during both the priming and effector phases of immune reactions. The fine-tuning of IL-1 signaling hinges upon two distinct receptor types; the functional IL-1 receptor (IL-1R) 1 and the decoy IL-1R2, accompanied by ancillary molecules such as the IL-1R accessory protein (IL-1R3) and IL-1R antagonist. IL-1R1 signaling by IL-1β is critical for the differentiation, expansion, and survival of Th17 cells, essential for defense against extracellular bacteria or fungi, yet implicated in autoimmune disease pathogenesis. Recent investigations emphasize the physiological importance of IL-1R2 expression, particularly in its capacity to modulate IL-1-dependent responses within Tregs. The precise regulation of IL-1R signaling is indispensable for orchestrating appropriate immune responses, as unchecked IL-1 signaling has been implicated in inflammatory disorders, including Th17-mediated autoimmunity. This review provides a thorough exploration of the IL-1R signaling complex and its pivotal roles in immune regulation. Additionally, it highlights recent advancements elucidating the mechanisms governing the expression of IL-1R1 and IL-1R2, underscoring their contributions to fine-tuning IL-1 signaling. Finally, the review briefly touches upon therapeutic strategies targeting IL-1R signaling, with potential clinical applications.

Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.

Staphylococcus aureus is a significant bacterial pathogen in both community and hospital settings, and the escalation of antimicrobial-resistant strains is of immense global concern. Vaccination is an inviting long-term strategy to curb staphylococcal disease, but identification of an effective vaccine has proved to be challenging. Three well-characterized, ubiquitous, secreted immune evasion factors from the staphylococcal superantigen-like (SSL) protein family were selected for the development of a vaccine. Wild-type SSL3, 7 and 11, which inhibit signaling through Toll-like receptor 2, cleavage of complement component 5 and neutrophil function, respectively, were successfully combined into a stable, active fusion protein (PolySSL7311). Vaccination of mice with an attenuated form of the PolySSL7311 protein stimulated significantly elevated specific immunoglobulin G and splenocyte proliferation responses to each component relative to adjuvant-only controls. Vaccination with PolySSL7311, but not a mixture of the individual proteins, led to a > 102 reduction in S. aureus tissue burden compared with controls after peritoneal challenge. Comparable antibody responses were elicited after coadministration of the vaccine in either AddaVax (an analog of MF59) or an Alum-based adjuvant; but only AddaVax conferred a significant reduction in bacterial load, aligning with other studies that suggest both cellular and humoral immune responses are necessary for protective immunity to S. aureus. Anti-sera from mice immunized with PolySSL7311, but not individual proteins, partially neutralized the functional activities of SSL7. This study confirms the importance of these SSLs for the survival of S. aureus in vivo and suggests that PolySSL7311 is a promising vaccine candidate.

Vaccination arguably remains the only long-term strategy to limit the spread of S. aureus infections and its related antibiotic resistance. To date, however, all staphylococcal vaccines tested in clinical trials have failed. In this review, we propose that the failure of S. aureus vaccines is intricately linked to prior host exposure to S. aureus and the pathogen's capacity to evade adaptive immune defenses. We suggest that non-protective immune imprints created by previous exposure to S. aureus are preferentially recalled by SA vaccines, and IL-10 induced by S. aureus plays a unique role in shaping these non-protective anti-staphylococcal immune responses. We discuss how S. aureus modifies the host immune landscape, which thereby necessitates alternative approaches to develop successful staphylococcal vaccines.

Given the self-evident importance of cutaneous immunity in the maintenance of body-surface homeostasis, disturbance of the steady-state skin is inextricably intertwined with dysfunction in cutaneous immunity. It is often overlooked by people that skin, well-known as a solid physical barrier, is also a strong immunological barrier, considering the abundant presence of immune cells including lymphocytes, granulocytes, dendritic cells, and macrophages. What's more, humoral immune components including cytokines, immunoglobulins, and antimicrobial peptides are also rich in the skin. This review centers on skin inflammation (acute and chronic, infection and aseptic inflammation), wound healing, and skin cancer to elucidate the elaborate network of immune cells in skin diseases.

Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.

The skin provides an essential barrier for host defense through rapid action of multiple resident and recruited cell types, but the complex communication network governing these processes is incompletely understood. To define these cell-cell interactions more clearly, we performed an unbiased network analysis of mouse skin during invasive S. aureus infection and revealed a dominant role for CXCL12+ fibroblast subsets in neutrophil communication. These subsets predominantly reside in the reticular dermis, express adipocyte lineage markers, detect IL-17 and TNFα, and promote robust neutrophil recruitment through NFKBIZ-dependent release of CXCR2 ligands and CXCL12. Targeted deletion of Il17ra in mouse fibroblasts resulted in greatly reduced neutrophil recruitment and increased infection by S. aureus. Analogous human CXCL12+ fibroblast subsets abundantly express neutrophil chemotactic factors in psoriatic skin that are subsequently decreased upon therapeutic targeting of IL-17. These findings show that CXCL12+ dermal immune acting fibroblast subsets play a critical role in cutaneous neutrophil recruitment and host defense.

Infection at barrier sites, e.g., skin, activates local immune defenses that limit pathogen spread, while preserving tissue integrity. Phenotypically distinct γδ T cell populations reside in skin, where they shape immunity to cutaneous infection prior to onset of an adaptive immune response by conventional αβ CD4+ (TCD4+) and CD8+ (TCD8+) T cells. To examine the mechanisms used by γδ T cells to control cutaneous virus replication and tissue pathology, we examined γδ T cells after infection with vaccinia virus (VACV). Resident γδ T cells expanded and combined with recruited γδ T cells to control pathology after VACV infection. However, γδ T cells did not play a role in control of local virus replication or blockade of systemic virus spread. We identified a unique wound healing signature that has features common to, but also features that antagonize, the sterile cutaneous wound healing response. Tissue repair generally occurs after clearance of a pathogen, but viral wound healing started prior to the peak of virus replication in the skin. γδ T cells contributed to wound healing through induction of multiple cytokines/growth factors required for efficient wound closure. Therefore, γδ T cells modulate the wound healing response following cutaneous virus infection, maintaining skin barrier function to prevent secondary bacterial infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of skin and soft tissue infections worldwide. This microorganism has a wide range of antibiotics resistance, a fact that has made the treatment of infections caused by MRSA difficult. In this sense, antimicrobial photodynamic therapy (aPDT) with natural products has emerged as a good alternative in combating infections caused by antibiotic-resistant microorganisms. The objective of the present study was to evaluate the effects of aPDT with Brazilian green propolis against intradermal MRSA infection in a murine model. Initially, 24 Balb/c mice were infected intradermally in the ears with 1.5 × 108 colony-forming units of MRSA 43300. After infection, they were separated into 4 groups (6 animals per group) and treated with the vehicle, only Brazilian green propolis, only blue LED light or with the aPDT protocol (Brazilian green propolis + blue LED light). It was observed in this study that aPDT with Brazilian green propolis reduced the bacterial load at the site of infection. Furthermore, it was able to inhibit weight loss resulting from the infection, as well as modulate the inflammatory response through greater recruitment of polymorphonuclear cells/neutrophils to the infected tissue. Finally, aPDT induced an increase in the cytokines IL-17A and IL-12p70 in the draining retromaxillary lymph node. Thus, aPDT with Brazilian green propolis proved to be effective against intradermal MRSA infection in mice, reducing bacterial load and modulating the immune response in the animals. However, more studies are needed to assess whether such effects are repeated in humans.

Antrochoanal polyp (ACP) is a benign nasal mass of unknown etiology. Tight junctions (TJs) are essential to the epithelial barrier that protects the body from external damage. However, the phenotype of tight junction in ACP is currently unclear.

The samples were collected from 20 controls, 37 patients with ACP and 45 patients with chronic rhinosinusitis with nasal polyp (CRSwNP). Quantitative Real-Time PCR (qRT-PCR) and immunofluorescence staining (IF) were performed to analyze the expressions of TJs markers (ZO-1, claudin-3 and occludin) and ZEB1. hNEpCs were transfected with ZEB1 small interfering RNA (si-ZEB1) or ZEB1 over-expression plasmid (OE-ZEB1). qRT-PCR and Western blotting were used to determine the levels of TJs-related markers. Primary human nasal epithelial cells (hNECs) were stimulated with IL-17A and si-ZEB1, and the expression of epithelial barrier markers were measured by qRT-PCR and Western blotting.

Compared to the control group, ACP group showed a significant downregulation in both mRNA and protein levels of ZO-1, occludin, and claudin-3. Furthermore, disease severity correlates positively with the degree of disruption of tight junctions. In addition, higher expression levels of ZEB1, IL-17A, and IFN-γ were observed in the ACP group compared to controls. Overexpression of ZEB1 in hNEpCs led to impairments in the levels of ZO-1, occludin, and claudin-3, while silencing of ZEB1 expression was found to enhance the barrier function of epithelial cells. Finally, IL-17 stimulation of hNECs impaired the expression of TJs-associated molecules (ZO-1, occludin, and claudin-3), which was effectively reversed by the IL-17A + si-ZEB1 group.

The tight junctions in ACP were extremely damaged and were correlated with the severity of the disease. ZEB1 was involved in the pathogenesis of ACP mediated by IL-17A through regulating tight junctions.

The growth of antibiotic-resistant bacterial infections necessitates focusing on host-derived immunotherapies. γδ T cells are an unconventional T cell subset, making up a relatively small portion of healthy circulating lymphocytes but a substantially increased proportion in mucosal and epithelial tissues. γδ T cells are activated and expanded in response to bacterial infection, having the capability to produce proinflammatory cytokines to recruit neutrophils and clear infection. They also play a significant role in dampening immune response to control inflammation and protecting the host against secondary challenge, making them promising targets when developing immunotherapy. Importantly, γδ T cells have differential metabolic states influencing their cytokine profile and subsequent inflammatory capacity. Though these differential metabolic states have not been well studied or reviewed in the context of bacterial infection, they are critical in understanding the mechanistic underpinnings of the host's innate immune response. Therefore, this review will focus on the context-specific host defense conferred by γδ T cells during infection with Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, and Mycobacterium tuberculosis.

Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.

BACKGROUNDT cell responses are impaired in Staphylococcus aureus-infected children, highlighting a potential mechanism of immune evasion. This study tested the hypotheses that toxin-specific antibodies protect immune cells from bacterial killing and are associated with improved T cell function following infection.METHODSS. aureus-infected and healthy children (N = 33 each) were prospectively enrolled. During acute infection and convalescence, we quantified toxin-specific IgG levels by ELISA, antibody function using a cell killing assay, and functional T cell responses by ELISPOT.RESULTSThere were no differences in toxin-specific IgG levels or ability to neutralize toxin-mediated immune cell killing between healthy and acutely infected children, but antibody levels and function increased following infection. Similarly, T cell function, which was impaired during acute infection, improved following infection. However, the response to infection was highly variable; up to half of children did not have improved antibody or T cell function. Serum from children with higher α-hemolysin-specific IgG levels more strongly protected immune cells against toxin-mediated killing. Importantly, children whose serum more strongly protected against toxin-mediated killing also had stronger immune responses to infection, characterized by more elicited antibodies and greater improvement in T cell function following infection.CONCLUSIONThis study demonstrates that, despite T cell impairment during acute infection, S. aureus elicits toxin-neutralizing antibodies. Individual antibody responses and T cell recovery are variable. These findings also suggest that toxin-neutralizing antibodies protect antigen-presenting cells and T cells, thereby promoting immune recovery. Finally, failure to elicit toxin-neutralizing antibodies may identify children at risk for prolonged T cell suppression.FUNDINGNIH National Institute of Allergy and Infectious Diseases R01AI125489 and Nationwide Children's Hospital.

Recent technological advancements have enabled us to study the molecular features of cellular states at the single-cell level, providing unprecedented resolution for comprehending the identity and function of a cell. By applying these techniques across multiple time frames, tissues, and diseases, we can delve deeper into the mechanisms governing the development and functions of cell lineages. In this review, I focus on γδ T cells, which are a unique and functionally nonredundant T cell lineage categorized under the umbrella of unconventional T cells. I discuss how single-cell biology is providing unique insights into their development and functions. Furthermore, I explore how single-cell methods can be used to answer several key questions about their biology. These investigations will be essential to fully understand their translational potential, including their role in cytotoxicity and tissue repair in cancer and regeneration.

Bacillus Calmette-Guérin vaccine is well known for inducing trained immunity in myeloid and natural killer cells, which can explain its cross-protective effect against heterologous infections. Although displaying functional characteristics of both adaptive and innate immunity, γδ T-cell memory has been only addressed in a pathogen-specific context. In this study, we aimed to determine whether human γδ T cells can mount trained immunity and therefore contribute to the cross-protective effect of the Bacillus Calmette-Guérin vaccine. We investigated in vivo induction of innate memory in γδ T cells by Bacillus Calmette-Guérin vaccination in healthy human volunteers by combining single-cell RNA sequencing technology with immune functional assays. The total number of γδ T cells and membrane markers of activation was not influenced by Bacillus Calmette-Guérin vaccination. In contrast, Bacillus Calmette-Guérin changed γδ T cells' transcriptional programs and increased their responsiveness to heterologous bacterial and fungal stimuli, including lipopolysaccharide and Candida albicans, as simultaneously characterized by higher tumor necrosis factor and interferon γ production, weeks after vaccination. Human γδ T cells in adults display the potential to develop a trained immunity phenotype after Bacillus Calmette-Guérin vaccination.

Interleukin-17 s (IL-17s) are well-known proinflammatory cytokines, and their antagonists perform excellently in the treatment of inflammatory skin diseases such as psoriasis. However, their physiological functions have not been given sufficient attention by clinicians. IL-17s can protect the host from extracellular pathogens, maintain epithelial integrity, regulate cognitive processes and modulate adipocyte activity through distinct mechanisms. Here, we present a systematic review concerning the physiological functions of IL-17s. Our goal is not to negate the therapeutic effect of IL-17 antagonists, but to ensure their safe use and reasonably explain the possible adverse events that may occur in their application.

Mastitis, a common disease for female during lactation period that could cause a health risk for human or huge economic losses for animals, is mainly caused by S. aureus invasion. Here, we found that neutrophil recruitment via IL-17A-mediated signaling was required for host defense against S. aureus-induced mastitis in a mouse model. The rapid accumulation and activation of Vγ4+ γδ T cells in the early stage of infection triggered the IL-17A-mediated immune response. Interestingly, the accumulation and influence of γδT17 cells in host defense against S. aureus-induced mastitis in a commensal microbiota-dependent manner. Overall, this study, focusing on γδT17 cells, clarified innate immune response mechanisms against S. aureus-induced mastitis, and provided a specific response to target for future immunotherapies. Meanwhile, a link between commensal microbiota community and host defense to S. aureus mammary gland infection may unveil potential therapeutic strategies to combat these intractable infections.

Cutaneous leishmaniasis causes alterations in the skin microbiota, leading to pathologic immune responses and delayed healing. However, it is not known how these microbiota-driven immune responses are regulated. Here, we report that depletion of Foxp3+ regulatory T cells (Tregs) in Staphylococcus aureus-colonized mice resulted in less IL-17 and an IFN-γ-dependent skin inflammation with impaired S. aureus immunity. Similarly, reducing Tregs in S. aureus-colonized and Leishmania braziliensis-infected mice increased IFN-γ, S. aureus, and disease severity. Importantly, analysis of lesions from L. braziliensis patients revealed that low FOXP3 gene expression is associated with high IFNG expression, S. aureus burden, and delayed lesion resolution compared to patients with high FOXP3 expression. Thus, we found a critical role for Tregs in regulating the balance between IL-17 and IFN-γ in the skin, which influences both bacterial burden and disease. These results have clinical ramifications for cutaneous leishmaniasis and other skin diseases associated with a dysregulated microbiome when Tregs are limited or dysfunctional.

Vision loss in patients with wet/exudative age-related macular degeneration (AMD) is associated with choroidal neovascularization (CNV), and AMD is the leading cause of irreversible vision impairment in older adults. Interleukin-17A (IL-17A) is a component of the microenvironment associated with some autoimmune diseases. Previous studies have indicated that wet AMD patients have elevated serum IL-17A levels. However, the effect of IL-17A on AMD progression needs to be better understood. We aimed to investigate the role of IL-17A in a laser-induced CNV mouse model.

We established a laser-induced CNV mouse model in wild-type (WT) and IL-17A-deficient mice and then evaluated the disease severity of these mice by using fluorescence angiography. We performed enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS) to analyze the levels of IL-17A and to investigate the immune cell populations in the eyes of WT and IL-17A-deficient mice. We used ARPE-19 cells to clarify the effect of IL-17A under oxidative stress.

In the laser-induced CNV model, the CNV lesions were larger in IL-17A-deficient mice than in WT mice. The numbers of γδ T cells, CD3+CD4+RORγt+ T cells, Treg cells, and neutrophils were decreased and the number of macrophages was increased in the eyes of IL-17A-deficient mice compared with WT mice. In WT mice, IL-17A-producing γδ T-cell numbers increased in a time-dependent manner from day 7 to 28 after laser injury. IL-6 levels increased and IL-10, IL-24, IL-17F, and GM-CSF levels decreased in the eyes of IL-17A-deficient mice after laser injury. In vitro, IL-17A inhibited apoptosis and induced the expression of the antioxidant protein HO-1 in ARPE-19 cells under oxidative stress conditions. IL-17A facilitated the repair of oxidative stress-induced barrier dysfunction in ARPE-19 cells.

Our findings provide new insight into the protective effect of IL-17A in a laser-induced CNV model and reveal a novel regulatory role of IL-17A-producing γδ T cells in the ocular microenvironment in wet AMD.