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1.
Int J Mol Sci ; 23(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36076953

RESUMO

Disruption of the skin microbial balance can exacerbate certain skin diseases and affect prognosis and treatment. Changes in the distribution and prevalence of certain microbial species on the skin, such as Staphylococcus aureus (SA), can impact the development of severe atopic dermatitis (AD) or psoriasis (Pso). A dysfunctional skin barrier develops in AD and Pso due to SA colonization, resulting in keratinization and chronic or progressive chronic inflammation. Disruption of the skin barrier following SA colonization can elevate the production of T helper 2 (Th2)-derived cytokines, which can cause an imbalance in Th1, Th2, and Th17 cells. This study examined the ability of potential therapeutic skin microbiomes, such as Cutibacterium avidum R-CH3 and Staphylococcus hominis R9, to inhibit SA biofilm formation and restore skin barrier function-related genes through the activation of the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid-2-related factor 2 (Nrf2) downstream target. We observed that IL-4/IL-13-induced downregulation of FLG, LOR, and IVL induced by SA colonization could be reversed by dual AhR/Nrf2 activation. Further, OVOL1 expression may be modulated by functional microbiomes via dual AhR/Nrf2 activation. Our results suggest that our potential therapeutic skin microbiomes can prevent SA-derived Th2-biased skin barrier disruption via IL-13 and IL-4-dependent FLG deregulation, STAT3 activation, and AhR-mediated STAT6 expression.


Assuntos
Microbiota , Psoríase , Receptores de Hidrocarboneto Arílico , Staphylococcus aureus , Humanos , Imunidade , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Proteínas de Filamentos Intermediários/genética , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Psoríase/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo
2.
Front Cell Infect Microbiol ; 12: 898796, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909964

RESUMO

Calprotectin is a transition metal chelating protein of the innate immune response known to exert nutritional immunity upon microbial infection. It is abundantly released during inflammation and is therefore found at sites occupied by pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. The metal limitation induced by this protein has previously been shown to mediate P. aeruginosa and S. aureus co-culture. In addition to the transition metal sequestration role of calprotectin, it has also been shown to have metal-independent antimicrobial activity via direct cell contact. Therefore, we sought to assess the impact of this protein on the biofilm architecture of P. aeruginosa and S. aureus in monomicrobial and polymicrobial culture. The experiments described in this report reveal novel aspects of calprotectin's interaction with biofilm communities of P. aeruginosa and S. aureus discovered using scanning electron microscopy and confocal laser scanning microscopy. Our results indicate that calprotectin can interact with microbial cells by stimulating encapsulation in mesh-like structures. This physical interaction leads to compositional changes in the biofilm extracellular polymeric substance (EPS) in both P. aeruginosa and S. aureus.


Assuntos
Biofilmes , Imunidade Inata , Complexo Antígeno L1 Leucocitário , Pseudomonas aeruginosa , Staphylococcus aureus , Antibacterianos/imunologia , Antibacterianos/farmacologia , Matriz Extracelular de Substâncias Poliméricas/genética , Matriz Extracelular de Substâncias Poliméricas/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Complexo Antígeno L1 Leucocitário/genética , Complexo Antígeno L1 Leucocitário/imunologia , Fagocitose , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/imunologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia
3.
Proc Natl Acad Sci U S A ; 119(25): e2116027119, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35704759

RESUMO

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.


Assuntos
Epiderme , Imunidade Inata , Dermatopatias Bacterianas , Animais , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Relógios Circadianos/imunologia , Epiderme/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Queratinócitos/imunologia , Mamíferos , Camundongos , Dermatopatias Bacterianas/imunologia , Dermatopatias Bacterianas/metabolismo , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia
4.
J Immunol ; 208(5): 1170-1179, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35140134

RESUMO

Mucosa-associated invariant T (MAIT) cells recognize bacterial riboflavin metabolite Ags presented by MHC class Ib-related protein (MR1) and play important roles in immune control of microbes that synthesize riboflavin. This includes the pathobiont Staphylococcus aureus, which can also express a range of virulence factors, including the secreted toxin leukocidin ED (LukED). In this study, we found that human MAIT cells are hypersensitive to LukED-mediated lysis and lost on exposure to the toxin, leaving a T cell population devoid of MAIT cells. The cytolytic effect of LukED on MAIT cells was rapid and occurred at toxin concentrations lower than those required for toxicity against conventional T cells. Furthermore, this coincided with high MAIT cell expression of CCR5, and loss of these cells was efficiently inhibited by the CCR5 inhibitor maraviroc. Interestingly, exposure and preactivation of MAIT cells with IL-12 and IL-18, or activation via TCR triggering, partially protected from LukED toxicity. Furthermore, analysis of NK cells indicated that LukED targeted the mature cytotoxic CD57+ NK cell subset in a CCR5-independent manner. Overall, these results indicate that LukED efficiently eliminates immune cells that can respond rapidly to S. aureus in an innate fashion without the need for clonal expansion, and that MAIT cells are exceptionally vulnerable to this toxin. Thus, the findings support a model where LukED secretion may allow S. aureus to avoid recognition by the rapid cell-mediated responses mediated by MAIT cells and NK cells.


Assuntos
Evasão da Resposta Imune/imunologia , Células Matadoras Naturais/imunologia , Leucocidinas/metabolismo , Células T Invariantes Associadas à Mucosa/patologia , Receptores CCR5/metabolismo , Staphylococcus aureus/patogenicidade , Antagonistas dos Receptores CCR5/farmacologia , Linhagem Celular , Humanos , Subunidade p35 da Interleucina-12/metabolismo , Interleucina-18/metabolismo , Ativação Linfocitária/imunologia , Maraviroc/farmacologia , Células T Invariantes Associadas à Mucosa/imunologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/imunologia , Células THP-1 , Fatores de Virulência/metabolismo
5.
Arterioscler Thromb Vasc Biol ; 42(3): 261-276, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35109674

RESUMO

Over the past 10 years, neutrophil extracellular traps (NETs) have become widely accepted as an integral player in immunothrombosis, due to their complex interplay with both pathogens and components of the coagulation system. While the release of NETs is an attempt by neutrophils to trap pathogens and constrain infections, NETs can have bystander effects on the host by inducing uncontrolled thrombosis, inflammation, and tissue damage. From an evolutionary perspective, pathogens have adapted to bypass the host innate immune response. Staphylococcus aureus (S. aureus), in particular, proficiently overcomes NET formation using several virulence factors. Here we review mechanisms of NET formation and how these are intertwined with platelet activation, the release of endothelial von Willebrand factor, and the activation of the coagulation system. We discuss the unique ability of S. aureus to modulate NET formation and alter released NETs, which helps S. aureus to escape from the host's defense mechanisms. We then discuss how platelets and the coagulation system could play a role in NET formation in S. aureus-induced infective endocarditis, and we explain how targeting these complex cellular interactions could reveal novel therapies to treat this disease and other immunothrombotic disorders.


Assuntos
Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/microbiologia , Staphylococcus aureus/patogenicidade , /etiologia , Animais , Fatores de Coagulação Sanguínea/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Evasão da Resposta Imune , Camundongos , Modelos Cardiovasculares , Modelos Imunológicos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Ativação Plaquetária , Infecções Estafilocócicas/complicações , Staphylococcus aureus/imunologia , /microbiologia , Fatores de Virulência/imunologia , Fator de von Willebrand/imunologia
6.
PLoS Pathog ; 18(2): e1010240, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35143595

RESUMO

Staphylococcus aureus bacteremia (SAB) remains a clinically challenging infection despite extensive investigation. Repurposing medications approved for other indications is appealing as clinical safety profiles have already been established. Ticagrelor, a reversible adenosine diphosphate receptor antagonist that prevents platelet aggregation, is indicated for patients suffering from acute coronary syndrome (ACS). However, some clinical data suggest that patients treated with ticagrelor are less likely to have poor outcomes due to S. aureus infection. There are several potential mechanisms by which ticagrelor may affect S. aureus virulence. These include direct antibacterial activity, up-regulation of the innate immune system through boosting platelet-mediated S. aureus killing, and prevention of S. aureus adhesion to host tissues. In this Pearl, we review the clinical data surrounding ticagrelor and infection as well as explore the evidence surrounding these proposed mechanisms of action. While more evidence is needed before antiplatelet medications formally become part of the arsenal against S. aureus infection, these potential mechanisms represent exciting pathways to target in the host/pathogen interface.


Assuntos
Bacteriemia/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Ticagrelor/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Inibidores da Agregação Plaquetária/uso terapêutico , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia
7.
Cell Immunol ; 372: 104483, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35085880

RESUMO

The occurring in SR-A/CD204- or CD36-deficient mice increased susceptibility to infections with Staphylococcus aureus (Sa) had traditionally been ascribed to the impairment of macrophage-mediated phagocytosis, which is, however, inconsistent with low effectiveness of unopsonized Sa killing within macrophages and redundant roles of both receptors in this process. We have found that Sa-stimulated cytokine production in mouse macrophages seems to be exclusively mediated by TLR2, mainly from within endosomes in response to Sa-derived lipoteichoic acid. By driving endocytic trafficking of TLR2 and its ligands through the clathrin-dependent pathway, CD36 and SR-A sensitize macrophages to activation by Sa as well as regulate the type and amount of cytokines produced. Additionally, upon direct Sa binding, both receptors autonomously generate anti-inflammatory signaling. Consequently, the delayed induction of acute inflammation in knockout mice may allow for the initial, uncontrolled multiplication of bacteria, stimulating excessive, septic shock-inducing production of inflammatory cytokines in later stages of infection.


Assuntos
Antígenos CD36/imunologia , Citocinas/biossíntese , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/microbiologia , Receptores Depuradores Classe A/imunologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Animais , Antígenos CD36/deficiência , Antígenos CD36/genética , Endocitose/imunologia , Ligantes , Receptores de Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Reconhecimento de Padrão/imunologia , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia
8.
Int J Mol Sci ; 23(2)2022 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-35055134

RESUMO

The main purpose of this review is to present justification for the urgent need to implement specific prophylaxis of invasive Staphylococcus aureus infections. We emphasize the difficulties in achieving this goal due to numerous S. aureus virulence factors important for the process of infection and the remarkable ability of these bacteria to avoid host defense mechanisms. We precede these considerations with a brief overview of the global necessitiy to intensify the use of vaccines against other pathogens as well, particularly in light of an impasse in antibiotic therapy. Finally, we point out global trends in research into modern technologies used in the field of molecular microbiology to develop new vaccines. We focus on the vaccines designed to fight the infections caused by S. aureus, which are often resistant to the majority of available therapeutic options.


Assuntos
Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/uso terapêutico , Staphylococcus aureus/imunologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Infecções Estafilocócicas/imunologia , Vacinas Antiestafilocócicas/imunologia , Vacinas Antiestafilocócicas/farmacologia , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Fatores de Virulência/genética , Fatores de Virulência/imunologia
9.
Elife ; 112022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34989676

RESUMO

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and potential treatment of biofilm-related infections. Here, we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. The mAbs were also shown to bind a collection of clinical isolates derived from different biofilm-associated infections (endocarditis, prosthetic joint, catheter). We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. Furthermore, we show that a mAb recognizing wall teichoic acid (clone 4497) specifically localizes to a subcutaneously implanted pre-colonized catheter in mice. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Biofilmes , Staphylococcus aureus/imunologia , Animais , Infecções Relacionadas a Cateter/imunologia , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/terapia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções Estafilocócicas/microbiologia , Ácidos Teicoicos/imunologia , Ácidos Teicoicos/metabolismo
10.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35058363

RESUMO

Gram-positive organisms with their thick envelope cannot be lysed by complement alone. Nonetheless, antibody-binding on the surface can recruit complement and mark these invaders for uptake and killing by phagocytes, a process known as opsonophagocytosis. The crystallizable fragment of immunoglobulins (Fcγ) is key for complement recruitment. The cell surface of S. aureus is coated with Staphylococcal protein A (SpA). SpA captures the Fcγ domain of IgG and interferes with opsonization by anti-S. aureus antibodies. In principle, the Fcγ domain of therapeutic antibodies could be engineered to avoid the inhibitory activity of SpA. However, the SpA-binding site on Fcγ overlaps with that of the neonatal Fc receptor (FcRn), an interaction that is critical for prolonging the half-life of serum IgG. This evolutionary adaptation poses a challenge for the exploration of Fcγ mutants that can both weaken SpA-IgG interactions and retain stability. Here, we use both wild-type and transgenic human FcRn mice to identify antibodies with enhanced half-life and increased opsonophagocytic killing in models of S. aureus infection and demonstrate that antibody-based immunotherapy can be improved by modifying Fcγ. Our experiments also show that by competing for FcRn-binding, staphylococci effectively reduce the half-life of antibodies during infection. These observations may have profound impact in treating cancer, autoimmune, and asthma patients colonized or infected with S. aureus and undergoing monoclonal antibody treatment.


Assuntos
Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Engenharia de Proteínas , Sequência de Aminoácidos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Ativação do Complemento , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Humanos , Fagocitose/imunologia , Ligação Proteica , Engenharia de Proteínas/métodos , Domínios e Motivos de Interação entre Proteínas/genética , Domínios e Motivos de Interação entre Proteínas/imunologia , Receptores Fc/genética , Proteína Estafilocócica A/imunologia , Staphylococcus aureus/imunologia
11.
PLoS Pathog ; 18(1): e1010227, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35041705

RESUMO

The blood-clotting protein fibrin(ogen) plays a critical role in host defense against invading pathogens, particularly against peritoneal infection by the Gram-positive microbe Staphylococcus aureus. Here, we tested the hypothesis that direct binding between fibrin(ogen) and S. aureus is a component of the primary host antimicrobial response mechanism and prevention of secondary microbe dissemination from the peritoneal cavity. To establish a model system, we showed that fibrinogen isolated from FibγΔ5 mice, which express a mutant form lacking the final 5 amino acids of the fibrinogen γ chain (termed fibrinogenγΔ5), did not support S. aureus adherence when immobilized and clumping when in suspension. In contrast, purified wildtype fibrinogen supported robust adhesion and clumping that was largely dependent on S. aureus expression of the receptor clumping factor A (ClfA). Following peritoneal infection with S. aureus USA300, FibγΔ5 mice displayed worse survival compared to WT mice coupled to reduced bacterial killing within the peritoneal cavity and increased dissemination of the microbes into circulation and distant organs. The failure of acute bacterial killing, but not enhanced dissemination, was partially recapitulated by mice infected with S. aureus USA300 lacking ClfA. Fibrin polymer formation and coagulation transglutaminase Factor XIII each contributed to killing of the microbes within the peritoneal cavity, but only elimination of polymer formation enhanced systemic dissemination. Host macrophage depletion or selective elimination of the fibrin(ogen) ß2-integrin binding motif both compromised local bacterial killing and enhanced S. aureus systemic dissemination, suggesting fibrin polymer formation in and of itself was not sufficient to retain S. aureus within the peritoneal cavity. Collectively, these findings suggest that following peritoneal infection, the binding of S. aureus to stabilized fibrin matrices promotes a local, macrophage-mediated antimicrobial response essential for prevention of microbe dissemination and downstream host mortality.


Assuntos
Fibrinogênio/imunologia , Peritonite/imunologia , Infecções Estafilocócicas/imunologia , Animais , Coagulase/imunologia , Coagulase/metabolismo , Fibrina/metabolismo , Camundongos , Peritonite/metabolismo , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo
12.
Shock ; 57(1): 72-80, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265830

RESUMO

ABSTRACT: Vitamin C combined with hydrocortisone is increasingly being used to treat septic patients, even though this treatment regimen is based on questionable evidence. When used, a marked effect on key players of innate immunity would be expected, as sepsis is featured by a dysregulated immune response.Here, we explored the effect of vitamin C and hydrocortisone alone and combined, in an ex vivo human whole-blood model of Escherichia coli- or Staphylococcus aureus-induced inflammation. Inflammatory markers for activation of complement (terminal C5b-9 complement complex [TCC]), granulocytes (myeloperoxidase), platelets (ß-thromboglobulin), cytokines (tumor necrosis factor [TNF], IL-1ß, IL6, and IL-8), and leukocytes (CD11b and oxidative burst) were quantified, by enzyme-linked immunosorbent assay, multiplex technology, and flow cytometry.In E. coli- and S. aureus-stimulated whole blood, a broad dose-titration of vitamin C and hydrocortisone alone did not lead to dose-response effects for the central innate immune mediators TCC and IL-6. Hence, the clinically relevant doses were used further. Compared to the untreated control sample, two of the nine biomarkers induced by E. coli were reduced by hydrocortisone and/or vitamin C. TNF was reduced by hydrocortisone alone (19%, P = 0.01) and by the combination (31%, P = 0.01). The oxidative burst of monocytes and granulocytes was reduced for both drugs alone and their combination, (ranging 8-19%, P < 0.05). Using S. aureus, neither of the drugs, alone nor in combination, had any effects on the nine biomarkers.In conclusion, despite the limitation of the ex vivo model, the effect of vitamin C and hydrocortisone on bacteria-induced inflammatory response in human whole blood is limited and following the clinical data.


Assuntos
Ácido Ascórbico/farmacologia , Escherichia coli/imunologia , Hidrocortisona/farmacologia , Staphylococcus aureus/imunologia , Biomarcadores , Antígeno CD11b/sangue , Complexo de Ataque à Membrana do Sistema Complemento/análise , Citocinas/sangue , Humanos , Peroxidase/sangue , Explosão Respiratória , beta-Tromboglobulina/análise
13.
Blood ; 139(8): 1222-1233, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-34814186

RESUMO

The newly identified 13-series (T-series) resolvins (RvTs) regulate phagocyte functions and accelerate resolution of infectious inflammation. Because severe acute respiratory syndrome coronavirus 2 elicits uncontrolled inflammation involving neutrophil extracellular traps (NETs), we tested whether stereochemically defined RvTs regulate NET formation. Using microfluidic devices capturing NETs in phorbol 12-myristate 13-acetate-stimulated human whole blood, the RvTs (RvT1-RvT4; 2.5 nM each) potently reduced NETs. With interleukin-1ß-stimulated human neutrophils, each RvT dose and time dependently decreased NETosis, conveying ∼50% potencies at 10 nM, compared with a known NETosis inhibitor (10 µM). In a murine Staphylococcus aureus infection, RvTs (50 ng each) limited neutrophil infiltration, bacterial titers, and NETs. In addition, each RvT enhanced NET uptake by human macrophages; RvT2 was the most potent of the four RvTs, giving a >50% increase in NET-phagocytosis. As part of the intracellular signaling mechanism, RvT2 increased cyclic adenosine monophosphate and phospho-AMP-activated protein kinase (AMPK) within human macrophages, and RvT2-stimulated NET uptake was abolished by protein kinase A and AMPK inhibition. RvT2 also stimulated NET clearance by mouse macrophages in vivo. Together, these results provide evidence for novel pro-resolving functions of RvTs, namely reducing NETosis and enhancing macrophage NET clearance via a cyclic adenosine monophosphate-protein kinase A-AMPK axis. Thus, RvTs open opportunities for regulating NET-mediated collateral tissue damage during infection as well as monitoring NETs.


Assuntos
Armadilhas Extracelulares/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , COVID-19/imunologia , Humanos , Inflamação/imunologia , Macrófagos/imunologia , Camundongos , Neutrófilos/imunologia , Fagocitose , SARS-CoV-2/imunologia
14.
Allergol Int ; 71(1): 31-39, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34838450

RESUMO

The skin microbiome is a key component of pathogenesis in atopic dermatitis (AD). The skin of AD patients is characterized by microbial dysbiosis, with a reduction of microbial diversity and overrepresentation of pathogenic Staphylococcus aureus (S. aureus). Recent exciting studies have elucidated an importance of establishing an appropriate immune response to microbes in early life and uncovered the new mechanisms of microbial community dynamics in modulating our skin microbiome. Several microbes are associated with AD pathogenesis, with proposed pathogenic effects from S. aureus and Malassezia. The complex relationships between microbes within the skin microbiome consortia includes various species, such as Staphylococcal, Roseomonas and Cutibacterium strains, that can inhibit S. aureus and are potential probiotics for AD skin. Numerous microbes are now also reported to modulate host response via communication with keratinocytes, specialized immune cells and adipocytes to improve skin health and barrier function. This increased understanding of skin microbiota bioactives has led to new biotherapeutic approaches that target the skin surface microenvironment for AD treatment.


Assuntos
Dermatite Atópica/microbiologia , Microbiota , Pele/microbiologia , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite Atópica/terapia , Feminino , Humanos , Masculino , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Exacerbação dos Sintomas , Adulto Jovem
15.
Nat Microbiol ; 7(1): 62-72, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34873293

RESUMO

Swift recruitment of phagocytic leucocytes is critical in preventing infection when bacteria breach through the protective layers of the skin. According to canonical models, this occurs via an indirect process that is initiated by contact of bacteria with resident skin cells and which is independent of the pathogenic potential of the invader. Here we describe a more rapid mechanism of leucocyte recruitment to the site of intrusion of the important skin pathogen Staphylococcus aureus that is based on direct recognition of specific bacterial toxins, the phenol-soluble modulins (PSMs), by circulating leucocytes. We used a combination of intravital imaging, ear infection and skin abscess models, and in vitro gene expression studies to demonstrate that this early recruitment was dependent on the transcription factor EGR1 and contributed to the prevention of infection. Our findings refine the classical notion of the non-specific and resident cell-dependent character of the innate immune response to bacterial infection by demonstrating a pathogen-specific high-alert mechanism involving direct recruitment of immune effector cells by secreted bacterial products.


Assuntos
Toxinas Bacterianas/imunologia , Linfócitos/imunologia , Infiltração de Neutrófilos/imunologia , Pele/imunologia , Pele/microbiologia , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Feminino , Humanos , Microscopia Intravital/métodos , Camundongos Endogâmicos C57BL , Staphylococcus aureus/patogenicidade , Fatores de Virulência
16.
Methods Mol Biol ; 2412: 439-447, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34918260

RESUMO

Staphylococcus aureus is a leading cause of community-acquired, healthcare-associated, and hospital-acquired infections. S. aureus bacteremia is a common and serious infection with significant morbidity and mortality in older patients. The rise of antibiotic-resistant strains of S. aureus has resulted in substantial loss and effective treatment in hospitalized patients. Thus, there is a need in the development of a vaccine that would provide protection against S. aureus. The antigens of our interest include proteins that are essential for bacterial attachment and colonization (ClfA and ClfB), dermonecrosis-driven toxin (Hla), antigens that are essential for abscess formation (EsxA and EsxB), and antigens that are essential for nutrient acquisition and resistance to phagocytes killing induced by reactive oxygen species (FhuD2 and MntC). Development of a structure-based vaccine based on the antigenic protein epitopes is a novel strategy to provide protection against S. aureus. Using bioinformatic tools, we have determined the B-cell and T-cell epitopes of the antigenic proteins of S. aureus. This chapter reports identification of B-cell and T-cell epitopes of the antigenic protein that could be used in the development of effective structure-based vaccines to protect against S. aureus.


Assuntos
Infecções Estafilocócicas , Vacinas , Idoso , Coagulase , Epitopos de Linfócito T , Humanos , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/imunologia , Vacinas Virais
17.
J Immunol ; 208(2): 454-463, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34930781

RESUMO

Inflammation involves a delicate balance between pathogen clearance and limiting host tissue damage, and perturbations in this equilibrium promote disease. Patients suffering from autoimmune diseases, such as systemic lupus erythematosus (SLE), have higher levels of serum S100A9 protein and increased risk for infection. S100A9 is highly abundant within neutrophils and modulates antimicrobial activity in response to bacterial pathogens. We reasoned that increased serum S100A9 in SLE patients reflects accumulation of S100A9 protein in neutrophils and may indicate altered neutrophil function. In this study, we demonstrate elevated S100A9 protein within neutrophils from SLE patients, and MRL/lpr mice associates with lower mitochondrial superoxide, decreased suicidal neutrophil extracellular trap formation, and increased susceptibility to Staphylococcus aureus infection. Furthermore, increasing mitochondrial superoxide production restored the antibacterial activity of MRL/lpr neutrophils in response to S. aureus These results demonstrate that accumulation of intracellular S100A9 associates with impaired mitochondrial homeostasis, thereby rendering SLE neutrophils inherently less bactericidal.


Assuntos
Calgranulina B/sangue , Armadilhas Extracelulares/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Mitocôndrias/metabolismo , Staphylococcus aureus/imunologia , Animais , Suscetibilidade a Doenças/imunologia , Feminino , Homeostase/fisiologia , Humanos , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/crescimento & desenvolvimento , Superóxidos/metabolismo
18.
Front Immunol ; 12: 732938, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34887850

RESUMO

Staphylococcal enterotoxin B (SEB) simultaneously crosslinks MHC class II antigen and TCR, promoting proliferation of T cells and releasing a large number of toxic cytokines. In this report, we computationally examined the possibility of using a single-chain biparatopic bispecific antibody to target SEB and prevent TCR binding. The design was inspired by the observation that mixing two anti-SEB antibodies 14G8 and 6D3 can block SEB-TCR activation, and we used 14G8-6D3-SEB tertiary crystal structure as a template. Twelve simulation systems were constructed to systematically examine the effects of the designed bispecific scFV MB102a, including isolated SEB, MB102a with different linkers, MB102a-SEB complex, MB102a-SEB-TCRß complex, MB102a-SEB-TCR-MHC II complex, and MB102a-SEB-MHC II. Our all atom molecular dynamics simulations (total 18,900 ns) confirmed that the designed single-chain bispecific antibody may allosterically prevent SEB-TCRß chain binding and inhibit SEB-TCR-MHC II formation. Subsequent analysis indicated that the binding of scFV to SEB correlates with SEB-TCR binding site motion and weakens SEB-TCR interactions.


Assuntos
Anticorpos Antibacterianos/imunologia , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/imunologia , Enterotoxinas/imunologia , Animais , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/genética , Anticorpos Biespecíficos/genética , Sítios de Ligação de Anticorpos , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Enterotoxinas/química , Humanos , Camundongos , Simulação de Dinâmica Molecular , Conformação Proteica , Engenharia de Proteínas , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Staphylococcus aureus/imunologia , Linfócitos T/imunologia , Linfócitos T/microbiologia
19.
Front Immunol ; 12: 790574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899759

RESUMO

Pseudomonas aeruginosa and Staphylococcus aureus are both opportunistic pathogens that are frequently associated with chronic lung infections. While bacterial virulence determinants are critical in initiating infection, the metabolic flexibility of these bacteria promotes their persistence in the airway. Upon infection, these pathogens induce host immunometabolic reprogramming, resulting in an airway milieu replete with immune-signaling metabolites. These metabolites are often toxic to the bacteria and create a steep selection pressure for the emergence of bacterial isolates adapted for long-term survival in the inflamed lung. In this review, we discuss the main differences in the host immunometabolic response to P. aeruginosa and S. aureus, as well as how these pathogens alter their own metabolism to adapt to airway metabolites and cause persistent lung infections.


Assuntos
Metabolismo Energético , Pulmão/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Infecções Respiratórias/metabolismo , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Adaptação Fisiológica , Animais , Interações Hospedeiro-Patógeno , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Succinatos/metabolismo
20.
Cells ; 10(12)2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34943933

RESUMO

Escherichia coli and Staphylococcus aureus are major mastitis causing pathogens in dairy cattle but elicit distinct immune and an inflammatory response in the udder. However, the host determinants responsible for this difference remains largely unknown. Our initial studies focused on the global transcriptomic response of primary bovine mammary epithelial cells (pbMECs) to heat-killed E. coli and S. aureus. RNA-sequencing transcriptome analysis demonstrates a significant difference in expression profiles induced by E. coli compared with S. aureus. A major differential response was the activation of innate immune response by E. coli, but not by S. aureus. Interestingly, E. coli stimulation increased transcript abundance of several genes downstream of Nrf2 (nuclear factor erythroid 2-related factor 2) that were enriched in gene sets with a focus on metabolism and immune system. However, none of these genes was dysregulated by S. aureus. Western blot analysis confirms that S. aureus impairs Nrf2 activation as compared to E. coli. Using Nrf2-knockdown cells we demonstrate that Nrf2 is necessary for bpMECs to mount an effective innate defensive response. In support of this notion, nuclear Nrf2 overexpression augmented S. aureus-stimulated inflammatory response. We also show that, unlike E. coli, S. aureus disrupts the non-canonical p62/SQSTM1-Keap1 pathway responsible for Nrf2 activation through inhibiting p62/SQSTM1 phosphorylation at S349. Collectively, our findings provide important insights into the contribution of the Nrf2 pathway to the pathogen-species specific immune response in bovine mammary epithelial cells and raise a possibility that impairment of Nrf2 activation contributes to, at least in part, the weak inflammatory response in S. aureus mastitis.


Assuntos
Imunidade Inata/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Mastite/genética , Fator 2 Relacionado a NF-E2/genética , Proteína Sequestossoma-1/genética , Animais , Bovinos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Escherichia coli/imunologia , Escherichia coli/patogenicidade , Feminino , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/microbiologia , Glândulas Mamárias Animais/patologia , Mastite/imunologia , Mastite/microbiologia , Mastite/patologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade
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