Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.230
Filtrar
1.
PLoS Pathog ; 16(8): e1008733, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817694

RESUMO

Staphylococcus aureus (S. aureus) is one of the most common bacterial infections worldwide, and antibiotic resistant strains such as Methicillin-Resistant S. aureus (MRSA) are a major threat and burden to public health. MRSA not only infects immunocompromised patients but also healthy individuals and has rapidly spread from the healthcare setting to the outside community. However, all vaccines tested in clinical trials to date have failed. Immunocompromised individuals such as patients with HIV or decreased levels of CD4+ T cells are highly susceptible to S. aureus infections, and they are also at increased risk of developing fungal infections. We therefore wondered whether stimulation of antifungal immunity might promote the type of immune responses needed for effective host defense against S. aureus. Here we show that vaccination of mice with a fungal ß-glucan particle (GP) loaded with S. aureus antigens provides protective immunity to S. aureus. We generated glucan particles loaded with the four S. aureus proteins ClfA, IsdA, MntC, and SdrE, creating the 4X-SA-GP vaccine. Vaccination of mice with three doses of 4X-SA-GP promoted protection in a systemic model of S. aureus infection with a significant reduction in the bacterial burden in the spleen and kidneys. 4X-SA-GP vaccination induced antigen-specific Th1 and Th17 CD4+ T cell and antibody responses and provided long-term protection. This work suggests that the GP vaccine system has potential as a novel approach to developing vaccines for S. aureus.


Assuntos
Saccharomyces cerevisiae/imunologia , Infecções Estafilocócicas/imunologia , Vacinas Antiestafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Coagulase/administração & dosagem , Coagulase/genética , Coagulase/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Saccharomyces cerevisiae/química , Infecções Estafilocócicas/microbiologia , Vacinas Antiestafilocócicas/administração & dosagem , Vacinas Antiestafilocócicas/genética , Staphylococcus aureus/genética , Células Th1/imunologia , Células Th17/imunologia , Vacinação , beta-Glucanas/administração & dosagem , beta-Glucanas/imunologia
2.
Artigo em Inglês | MEDLINE | ID: mdl-32637365

RESUMO

The airway epithelial barrier is a major barrier protecting against clinically significant infections of the lung. Its integrity is often compromised due to mechanical, chemical, or infectious causes. Opportunistic bacterial pathogens are poised to cause parenchymal infection and become difficult to eradicate due to adaptive metabolic changes, biofilm formation, and the acquisition of antimicrobial resistance and fitness genes. Enhancing mucosal defenses by modulating the cytokines that regulate barrier functions, such as interleukin-22 (IL-22) and interferon-λ (IFN-λ), members of the IL-10 family of cytokines, is an attractive approach to prevent these infections that are associated with high morbidity and mortality. These cytokines both signal through the cognate receptor IL-10RB, have related protein structures and common downstream signaling suggesting shared roles in host respiratory defense. They are typically co-expressed in multiple models of infections, but with differing kinetics. IL-22 has an important role in the producing antimicrobial peptides, upregulating expression of junctional proteins in the airway epithelium and working in concert with other inflammatory cytokines such as IL-17. Conversely, IFN-λ, a potent antiviral in influenza infection with pro-inflammatory properties, appears to decrease junctional integrity allowing for bacterial and immune cell translocation. The effects of these cytokines are pleotropic, with pathogen and tissue specific consequences. Understanding how these cytokines work in the mucosal defenses of the respiratory system may suggest potential targets to prevent invasive infections of the damaged lung.


Assuntos
Interferon gama/imunologia , Subunidade beta de Receptor de Interleucina-10/imunologia , Interleucinas/imunologia , Mucosa Respiratória/imunologia , Junções Íntimas/imunologia , Infecções por Coronavirus/imunologia , Humanos , Influenza Humana/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/imunologia , Pseudomonas aeruginosa/imunologia , Mucosa Respiratória/microbiologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia
3.
Mol Immunol ; 124: 211-217, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32603960

RESUMO

The primary immune response against Staphylococcus aureus is mediated by neutrophils. In response to S. aureus and its proteins, neutrophil shows two different kinds of NETosis, viz. suicidal and vesicular NETosis. Glucose is the major energy source of neutrophils for performing NETosis. However, NETosis was found altered in response to high glucose levels. Growth of S. aureus was also found modulated in response to high glucose and they behave differently at different glucose levels. This work was attempted to study NET release in response to S. aureus cell-free culture supernatant at different glucose concentrations. Freshly isolated neutrophils were treated with different concentrations of glucose along with S. aureus cell-free culture supernatant and were analyzed for neutrophil extracellular trap formation, ROS production, and peptidylarginine deiminase 4 activities. Influence of calcium on NETosis was analyzed using calcium chelator (EDTA) and calcium inhibitor (TMB-8). With increasing glucose levels, NET release in response to S. aureus cell-free culture supernatant was increased. Oxidant level was also increased dose-dependently with increasing concentrations of glucose. At very high glucose concentrations (> 15 mM), vesicular NETosis was predominantly observed. At these glucose concentrations, peptidylarginine deiminase activity was found to be decreased. Furthermore, calcium quenching in the medium facilitated vesicular mode of NET release. In conclusion, calcium depletion occurring at high glucose concentrations can reduce peptidylarginine deiminase 4 activity and can thereby promote the vesicular NET release.


Assuntos
Cálcio/metabolismo , Armadilhas Extracelulares/metabolismo , Glucose/metabolismo , Neutrófilos/imunologia , Staphylococcus aureus/imunologia , Células Cultivadas , Armadilhas Extracelulares/imunologia , Humanos , Vesículas Secretórias/metabolismo , Infecções Estafilocócicas/imunologia
4.
Nat Commun ; 11(1): 3334, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620760

RESUMO

TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.


Assuntos
Homeostase/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Intestinos/imunologia , Células Th17/imunologia , Animais , Plasticidade Celular/imunologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Células HEK293 , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
5.
PLoS One ; 15(6): e0234484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511271

RESUMO

Inflammation plays a crucial role in the defense response of the innate immune system against pathogen infection. In this study, we selected 4 compounds for their potential or proven anti-inflammatory and/or anti-microbial properties to test on our in vitro model of bacteria-infected THP-1-derived macrophages. We first compared the capacity of sulforaphane (SFN), wogonin (WG), oltipraz (OTZ), and dimethyl fumarate (DMF) to induce the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of the antioxidant, anti-inflammatory response pathways. Next, we performed a comparative evaluation of the antioxidant and anti-inflammatory efficacies of the 4 selected compounds. THP-1-derived macrophages and LPS-stimulated macrophages were treated with each compound and expression levels of genes coding for inflammatory cytokines IL-1ß, IL-6, and TNF-α were quantified by RT-qPCR. Moreover, expression levels of genes coding for M1 (IL-23, CCR7, IL-1ß, IL-6, and TNF-α) and M2 (PPARγ, MRC1, CCL22, and IL-10) markers were determined in classically-activated M1 macrophages treated with each compound. Finally, the effects of each compound on the intracellular bacterial survival of gram-negative E. coli and gram-positive S. aureus in THP-1-derived macrophages and PBMC-derived macrophages were examined. Our data confirmed the anti-inflammatory and antioxidant effects of SFN, WG, and DMF on LPS-stimulated THP-1-derived macrophages. In addition, SFN or WG treatment of classically-activated THP-1-derived macrophages reduced expression levels of M1 marker genes, while SFN or DMF treatment upregulated the M2 marker gene MRC1. This decrease in expression of M1 marker genes may be correlated with the decrease in intracellular S. aureus load in SFN- or DMF-treated macrophages. Interestingly, an increase in intracellular survival of E. coli in SFN-treated THP-1-derived macrophages that was not observed in PBMC-derived macrophages. Conversely, OTZ exhibited pro-oxidant and proinflammatory properties, and affected intracellular survival of E. coli in THP-1-derived macrophages. Altogether, we provide new potential therapeutic alternatives in treating inflammation and bacterial infection.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Estresse Oxidativo/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Flavanonas/farmacologia , Humanos , Inflamação/imunologia , Isotiocianatos/farmacologia , Leucócitos Mononucleares , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Estresse Oxidativo/imunologia , Pirazinas/farmacologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Células THP-1
6.
PLoS One ; 15(4): e0225873, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32352968

RESUMO

Black soldier fly (BSF; Hermetia illucens L.) larvae can convert fresh pig manure into protein and fat-rich biomass, which can then be used as aquafeed for select species. Currently, BSF is the only approved insect for such purposes in Canada, USA, and the European Union. Pig manure could serve as a feed substrate for BSF; however, it is contaminated with zoonotic pathogens (e.g., Staphylococcus aureus and Salmonella spp.). Fortunately, BSF larvae inhibit many of these zoonotic pathogens; however, the mechanisms employed are unclear. We employed RNAi, qRT-PCR, and Illumina MiSeq 16S rDNA high-throughput sequencing to examine the interaction between two immune genes (Duox in Duox-reactive oxygen species [ROS] immune system and TLR3 in the Toll signaling pathway) and select pathogens common in pig manure to decipher the mechanisms resulting in pathogen suppression. Results indicate Bsf Duox-TLR3 RNAi increased bacterial load but decreased relative abundance of Providencia and Dysgonomonas, which are thought to be commensals in the BSF larval gut. Bsf Duox-TLR3 RNAi also inactivated the NF-κB signaling pathway, downregulated the expression of antimicrobial peptides, and diminished inhibitory effects on zoonotic pathogen. The resulting dysbiosis stimulated an immune response by activating BsfDuox and promoting ROS, which regulated the composition and structure of the gut bacterial community. Thus, BsfDuox and BsfTLR3 are important factors in regulating these key gut microbes, while inhibiting target zoonotic pathogens.


Assuntos
Oxidases Duais/imunologia , Microbioma Gastrointestinal , Proteínas de Insetos/imunologia , Esterco/microbiologia , Simuliidae/imunologia , Receptor 3 Toll-Like/imunologia , Animais , Homeostase , Humanos , Larva/imunologia , Larva/microbiologia , Salmonella/imunologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Transdução de Sinais , Simuliidae/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Suínos , Zoonoses/imunologia , Zoonoses/microbiologia
7.
BMC Infect Dis ; 20(1): 354, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32429852

RESUMO

BACKGROUND: Mediastinitis caused by hematogenous spread of an infection is rare. We report the first known case of community-acquired mediastinitis from hematogenous origin in an immunocompetent adult. This rare invasive infection was due to Panton-Valentine Leucocidin-producing (PVL+) methicillin-susceptible Staphylococcus aureus (MSSA). CASE PRESENTATION: A 22-year-old obese man without other medical history was hospitalized for febrile precordial chest pain. He reported a cutaneous back abscess 3 weeks before. CT-scan was consistent with mediastinitis and blood cultures grew for a PVL+ MSSA. Intravenous clindamycin (600 mg t.i.d) and cloxacillin (2 g q.i.d.), secondary changed for fosfomycin (4 g q.i.d.) because of a related toxidermia, was administered. Surgical drainage was performed and confirmed the presence of a mediastinal abscess associated with a fistula between the mediastinum and right pleural space. All local bacteriological samples also grew for PVL+ MSSA. In addition to clindamycin, intravenous fosfomycin was switched to trimethoprim-sulfamethoxazole after 4 weeks for a total of 10 weeks of antibiotics. CONCLUSIONS: We present the first community-acquired mediastinitis of hematogenous origin with PVL+ MSSA. Clinical evolution was favorable after surgical drainage and 10 weeks of antibiotics. The specific virulence of MSSA PVL+ strains played presumably a key role in this rare invasive clinical presentation.


Assuntos
Toxinas Bacterianas/análise , Infecções Comunitárias Adquiridas/diagnóstico , Exotoxinas/análise , Imunocompetência , Leucocidinas/análise , Mediastinite/diagnóstico , Mediastinite/microbiologia , Infecções Estafilocócicas/diagnóstico , Staphylococcus aureus/metabolismo , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Abscesso/cirurgia , Antibacterianos/uso terapêutico , Anti-Infecciosos Urinários/uso terapêutico , Clindamicina/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Drenagem , Humanos , Masculino , Mediastinite/tratamento farmacológico , Mediastinite/imunologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Adulto Jovem
8.
PLoS Pathog ; 16(4): e1008443, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32343740

RESUMO

Staphylococcus aureus (SA) is the causative agent of both skin/soft tissue infections as well as invasive bloodstream infections. Though vaccines have been developed to target both humoral and T cell-mediated immune responses against SA, they have largely failed due to lack of protective efficacy. Group 1 CD1-restricted T cells recognize lipid rather than peptide antigens. Previously found to recognize lipids derived from cell wall of Mycobacterium tuberculosis (Mtb), these cells were associated with protection against Mtb infection in humans. Using a transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg), we demonstrate that group 1 CD1-restricted T cells can recognize SA-derived lipids in both immunization and infection settings. Systemic infection of hCD1Tg mice showed that SA-specific group 1 CD1-restricted T cell response peaked at 10 days post-infection, and hCD1Tg mice displayed significantly decreased kidney pathology at this time point compared with WT control mice. Immunodominant SA lipid antigens recognized by group 1 CD1-restricted T cells were comprised mainly of cardiolipin and phosphatidyl glycerol, with little contribution from lysyl-phosphatidyl glycerol which is a unique bacterial lipid not present in mammals. Group 1 CD1-restricted T cell lines specific for SA lipids also conferred protection against SA infection in the kidney after adoptive transfer. They were further able to effectively control SA replication in vitro through direct antigen presentation by group 1 CD1-expressing BMDCs. Together, our data demonstrate a previously unknown role for group 1 CD1-restricted SA lipid-specific T cells in the control of systemic MRSA infection.


Assuntos
Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD1/genética , Antígenos CD1/imunologia , Humanos , Imunização , Rim/imunologia , Rim/microbiologia , Lipídeos/imunologia , Camundongos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia
9.
PLoS One ; 15(3): e0229908, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155184

RESUMO

We have previously shown that changes in the microbiome influence how the healing tendon responds to different treatments. The aim of this study was to investigate if changes in the microbiome influence the response to mechanical loading during tendon healing. 90 Sprague-Dawley rats were used. Specific Opportunist and Pathogen Free (SOPF) rats were co-housed with Specific Pathogen Free (SPF) rats, carrying Staphylococcus aureus and other opportunistic microbes. After 6 weeks of co-housing, the SOPF rats were contaminated which was confirmed by Staphylococcus aureus growth. Clean SOPF rats were used as controls. The rats were randomized to full loading or partial unloading by Botox injections in their calf muscles followed by complete Achilles tendon transection. Eight days later, the healing tendons were tested mechanically. The results were analysed by a 2-way ANOVA with interaction between loading and contamination on peak force as the primary outcome and there was an interaction for both peak force (p = 0.049) and stiffness (p = 0.033). Furthermore, partial unloading had a profound effect on most outcome variables. In conclusion, the response to mechanical loading during tendon healing is influenced by changes in the microbiome. Studies aiming for clinical relevance should therefore consider the microbiome of laboratory animals.


Assuntos
Tendão do Calcâneo/lesões , Fenômenos Biomecânicos/imunologia , Modelos Animais de Doenças , Microbiota/imunologia , Cicatrização/imunologia , Animais , Feminino , Humanos , Infecções Oportunistas/imunologia , Infecções Oportunistas/microbiologia , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos/imunologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Estresse Mecânico
10.
J Dairy Sci ; 103(5): 4588-4605, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32113759

RESUMO

Staphylococcus aureus is one of the pathogens most frequently isolated from cases of mastitis worldwide. To decrease the effect of S. aureus mastitis in dairy farming, alternative strategies for controlling mastitis are needed that depend on a better knowledge of cow-to-cow variations in S. aureus antibody production. The present study sought to explore the diversity of S. aureus antibodies produced by dairy cows with a distinct mastitis history and vaccinated with a polyvalent mastitis vaccine. We obtained protein extracts from S. aureus isolates derived from persistent subclinical mastitis. Proteins were fractionated using 2-dimensional gel electrophoresis and Western blotting. Then, Western blotting membranes were exposed to sera from 24 dairy cows that had been divided into the following groups: vaccinated dairy cows that were infected with S. aureus, further subdivided according to whether they (a) remained infected by S. aureus or (b) recovered from the intramammary infection; unvaccinated dairy cows infected with S. aureus; and vaccinated healthy dairy cows with no history of S. aureus mastitis. Proteins found to be reactive by Western blot were identified by mass spectrometry (MALDI/TOF-TOF). Our most important finding was that F0F1 ATP synthase subunit α, succinyl-diaminopimelate desuccinylase, and cysteinyl-tRNA synthetase were potential candidate proteins for the prevention of S. aureus mastitis. This study strengthens the notion that variations among animals should not be ignored and shows that the heterogeneity of antibody production against anti-staphylococcal antigens in animals may enable the identification of new immunotherapy targets.


Assuntos
Anticorpos Antibacterianos/sangue , Mastite Bovina/imunologia , Infecções Estafilocócicas/veterinária , Vacinas Antiestafilocócicas/administração & dosagem , Staphylococcus aureus/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Bovinos , Feminino , Humanos , Mastite Bovina/microbiologia , Mastite Bovina/prevenção & controle , Leite , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Vacinas Antiestafilocócicas/imunologia
11.
Am J Pathol ; 190(6): 1151-1163, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32194053

RESUMO

Osteomyelitis is an inflammation of the bone and bone marrow that is most commonly caused by a Staphylococcus aureus infection. Much of our understanding of the underlying pathophysiology of osteomyelitis, from the perspective of both host and pathogen, has been revised in recent years, with notable discoveries including the role played by osteocytes in the recruitment of immune cells, the invasion and persistence of S. aureus in submicron channels of cortical bone, and the diagnostic role of polymorphonuclear cells in implant-associated osteomyelitis. Advanced in vitro cell culture models, such as ex vivo culture models or organoids, have also been developed over the past decade, and have become widespread in many fields, including infectious diseases. These models better mimic the in vivo environment, allow the use of human cells, and can reduce our reliance on animals in osteomyelitis research. In this review, we provide an overview of the main pathologic concepts in osteomyelitis, with a focus on the new discoveries in recent years. Furthermore, we outline the value of modern in vitro cell culture techniques, with a focus on their current application to infectious diseases and osteomyelitis in particular.


Assuntos
Osteomielite/imunologia , Osteomielite/patologia , Infecções Estafilocócicas/patologia , Animais , Modelos Animais de Doenças , Humanos , Osteócitos/patologia , Projetos de Pesquisa , Infecções Estafilocócicas/imunologia , Staphylococcus aureus
12.
Nat Commun ; 11(1): 1242, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144270

RESUMO

Expression of the matricellular protein CCN1 (CYR61) is associated with inflammation and is required for successful wound repair. Here, we show that CCN1 binds bacterial pathogen-associated molecular patterns including peptidoglycans of Gram-positive bacteria and lipopolysaccharides of Gram-negative bacteria. CCN1 opsonizes methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa and accelerates their removal by phagocytosis and increased production of bactericidal reactive oxygen species in macrophages through the engagement of integrin αvß3. Mice with myeloid-specific Ccn1 deletion and knock-in mice expressing CCN1 unable to bind αvß3 are more susceptible to infection by S. aureus or P. aeruginosa, resulting in increased mortality and organ colonization. Furthermore, CCN1 binds directly to TLR2 and TLR4 to activate MyD88-dependent signaling, cytokine expression and neutrophil mobilization. CCN1 is therefore a pattern recognition receptor that opsonizes bacteria for clearance and functions as a damage-associated molecular pattern to activate inflammatory responses, activities that contribute to wound healing and tissue repair.


Assuntos
Proteína Rica em Cisteína 61/metabolismo , Proteínas Opsonizantes/metabolismo , Infecções por Pseudomonas/imunologia , Infecções Estafilocócicas/imunologia , Receptores Toll-Like/metabolismo , Animais , Proteína Rica em Cisteína 61/genética , Proteína Rica em Cisteína 61/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Técnicas de Introdução de Genes , Técnicas de Silenciamento de Genes , Humanos , Integrina alfaVbeta3/imunologia , Integrina alfaVbeta3/metabolismo , Masculino , Staphylococcus aureus Resistente à Meticilina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Opsonizantes/genética , Padrões Moleculares Associados a Patógenos/metabolismo , Fagocitose/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/imunologia , Células Sf9 , Transdução de Sinais/imunologia , Infecções Estafilocócicas/microbiologia , Receptores Toll-Like/imunologia
13.
J Med Microbiol ; 69(4): 591-599, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32043953

RESUMO

Introduction. Staphylococcal enterotoxin B (SEB) is an extensively studied super-antigen. A previous study by us suggested that SEB exposure during pregnancy could alter the percentage of CD4+ and CD8+ T cells in the peripheral blood of neonatal offspring rats.Aim. It is unknown whether SEB exposure during pregnancy can influence the development of regulatory T cells (Tregs) in the peripheral blood of neonatal offspring rats.Methodology. Pregnant rats at gestational day 16 were intravenously injected with 15 µg SEB. Peripheral blood was acquired from neonatal offspring rats on days 1, 3 and 5 after delivery and from adult offspring rats for determination of Treg number by cytometry, cytokines by ELISA, and FoxP3 expression by real-time PCR and western blot.Results. SEB given to pregnant rats significantly increased the absolute number of Tregs and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in the peripheral blood of not only neonatal but also adult offspring rats. Furthermore, repeated SEB exposure in adult offspring rats significantly decreased the absolute number of Tregs (P<0.01), and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in their peripheral blood.Conclusion. Prenatal SEB exposure attenuates the development and function of Tregs to repeated SEB exposure in the peripheral blood of adult offspring rats.


Assuntos
Enterotoxinas/imunologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Infecções Estafilocócicas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Exposição Materna/efeitos adversos , Gravidez , Complicações na Gravidez/microbiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Linfócitos T Reguladores/citologia
14.
Sci Adv ; 6(4): eaax8820, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010784

RESUMO

Extreme pathophysiological stressors induce expansion of otherwise infrequent leukocyte populations. Here, we found a previously unidentified CD11b+Gr-1+ myeloid cell population that expresses stem cell antigen-1 (Sca-1) induced upon experimental infection with Staphylococcus aureus. Although CD11b+Gr-1+Sca-1+ cells have impaired migratory capacity and superoxide anion-producing activity, they secrete increased levels of several cytokines and chemokines compared to Sca-1- counterparts. The generation of CD11b+Gr-1+Sca-1+ cells is dependent on IFN-γ in vivo, and in vitro stimulation of bone marrow cells or granulocyte-macrophage progenitors with IFN-γ generated CD11b+Gr-1+Sca-1+ cells. Depletion of CD11b+Gr-1+Sca-1+ cells by administrating anti-Sca-1 antibody strongly increased survival rates in an S. aureus infection model by reducing organ damage and inflammatory cytokines. However, adoptive transfer of CD11b+Gr-1+Sca-1+ cells decreased survival rates by worsening the pathogenesis of S. aureus infection. Together, we found a previously unidentified pathogenic CD11b+Gr-1+Sca-1+ population that plays an essential role in mortality during bacterial infection.


Assuntos
Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Biomarcadores , Células Mieloides/imunologia , Transferência Adotiva , Animais , Antígenos Ly/metabolismo , Infecções Bacterianas/metabolismo , Antígeno CD11b/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Células Mieloides/metabolismo , Fenótipo , Prognóstico , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Staphylococcus aureus/imunologia , Superóxidos/metabolismo
15.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31932326

RESUMO

Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes a variety of diseases. Bloodstream infection is the most severe, with mortality rates reaching 20 to 50%. Exopolysaccharide (EPS) from the probiotic Bacillus subtilis reduces bacterial burden and inflammation during S. aureus bloodstream infection in mice. Protection is due, in part, to hybrid macrophages that restrict S. aureus growth through reactive oxygen species and to limiting superantigen-induced T cell activation and interferon gamma (IFN-γ) production during infection. A decrease in IFN-γ production was observed within 24 h after infection, and here, we investigated how EPS abrogates its production. We discovered that S. aureus uses a rapid, superantigen-independent mechanism to induce host IFN-γ and that this is mediated by interleukin-12 (IL-12) activation of NK cells. Furthermore, we found that EPS limits IFN-γ production by modulating host immunity in a Toll-like receptor 4 (TLR4)-dependent manner, a signaling pathway that is required for EPS-mediated protection from S. aureus infection in vivo We conclude that EPS protects hosts from acute bloodstream S. aureus infection not only by inducing macrophages that restrict S. aureus growth and inhibit superantigen-activated T cells but also by limiting NK cell production of IFN-γ after S. aureus infection in a TLR4-dependent manner.


Assuntos
Bacteriemia/prevenção & controle , Interferon gama/antagonistas & inibidores , Células Matadoras Naturais/imunologia , Polissacarídeos Bacterianos/administração & dosagem , Probióticos/administração & dosagem , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/imunologia , Animais , Bacteriemia/imunologia , Modelos Animais de Doenças , Fatores Imunológicos/administração & dosagem , Interleucina-12/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Infecções Estafilocócicas/imunologia , Análise de Sobrevida , Receptor 4 Toll-Like/metabolismo
16.
Hum Genet ; 139(6-7): 981-991, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31980906

RESUMO

Many bacteria can cause pyogenic lesions in humans. Most of these bacteria are harmless in most individuals, but they, nevertheless, cause significant morbidity and mortality worldwide. The inherited and acquired immunodeficiencies underlying these pyogenic infections differ between bacteria. This short review focuses on two emblematic pyogenic bacteria: pneumococcus (Streptococcus pneumoniae) and Staphylococcus, both of which are Gram-positive encapsulated bacteria. We will discuss the contribution of human genetic studies to the identification of germline mutations of the TLR and IL-1R pathways.


Assuntos
Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Infecções Pneumocócicas/genética , Polimorfismo Genético , Receptores de Interleucina-1/genética , Infecções Estafilocócicas/genética , Receptores Toll-Like/genética , Doenças Genéticas Inatas/imunologia , Genética Humana , Humanos , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus/patogenicidade , Streptococcus pneumoniae/patogenicidade , Virulência/genética
17.
APMIS ; 128(4): 275-286, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31976582

RESUMO

Bone infections are difficult to diagnose and treat, especially when a prosthetic joint replacement or implant is involved. Bone loss is a major complication of osteomyelitis, but the mechanism behind has mainly been investigated in cell cultures and has not been confirmed in human settings. Inflammation is important in initiating an appropriate immune response to invading pathogens. However, many of the signaling molecules used by the immune system can also modulate bone remodeling and contribute to bone resorption during osteomyelitis. Our current knowledge of the inflammatory response relies heavily on animal models as research based on human samples is scarce. Staphylococcus aureus is one of the most common causes of bone infections and is the pathogen of choice in animal models. The regulation of inflammatory genes during prosthetic joint infections and implant-associated osteomyelitis has only been studied in rodent models. It is important to consider the validity of an animal model when results are extrapolated to humans, and both bone composition and the immune system of pigs has been shown to be more similar to humans, than to rodents. Here in vivo studies on the inflammatory response to prosthetic joint infections and implant-associated osteomyelitis are reviewed.


Assuntos
Osso e Ossos/imunologia , Osso e Ossos/microbiologia , Inflamação/imunologia , Animais , Modelos Animais de Doenças , Humanos , Infecções Relacionadas à Prótese/imunologia , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia
18.
Emerg Microbes Infect ; 9(1): 169-179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31969071

RESUMO

Staphylococcus aureus (S. aureus), especially methicillin-resistant Staphylococcus aureus (MRSA), is a major cause of pneumonia, resulting in severe morbidity and mortality in adults and children. Sortase A (SrtA), which mediates the anchoring of cell surface proteins in the cell wall, is an important virulence factor of S. aureus. Here, we found that salvianolic acid A (Sal A), which is a natural product that does not affect the growth of S. aureus, could inhibit SrtA activity (IC50 = 5.75 µg/ml) and repress the adhesion of bacteria to fibrinogen, the anchoring of protein A to cell wall, the biofilm formation, and the ability of S. aureus to invade A549 cells. Furthermore, in vivo studies demonstrated that Sal A treatment reduced inflammation and protected mice against lethal pneumonia caused by MRSA. More significantly, full protection (a survival rate of 100%) was achieved when Sal A was administered in combination with latamoxef. Together, these results indicate that Sal A could be developed into a promising therapeutic drug to combat MRSA infections while limiting resistance development.


Assuntos
Ácidos Cafeicos/administração & dosagem , Lactatos/administração & dosagem , Staphylococcus aureus Resistente à Meticilina/fisiologia , Moxalactam/administração & dosagem , Pneumonia/prevenção & controle , Infecções Estafilocócicas/prevenção & controle , Aminoaciltransferases/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Cisteína Endopeptidases/metabolismo , Sinergismo Farmacológico , Feminino , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia
19.
J Immunol ; 204(4): 954-966, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31915259

RESUMO

Neutrophils are critical to the generation of effective immune responses and for killing invading microbes. Paired immune receptors provide important mechanisms to modulate neutrophil activation thresholds and effector functions. Expression of the leukocyte Ig-like receptor (LILR)A6 (ILT8/CD85b) and LILRB3 (ILT5/CD85a) paired-receptor system on human neutrophils has remained unclear because of the lack of specific molecular tools. Additionally, there is little known of their possible functions in neutrophil biology. The objective of this study was to characterize expression of LILRA6/LILRB3 receptors during human neutrophil differentiation and activation, and to assess their roles in modulating Fc receptor-mediated effector functions. LILRB3, but not LILRA6, was detected in human neutrophil lysates following immunoprecipitation by mass spectrometry. We demonstrate high LILRB3 expression on the surface of resting neutrophils and release from the surface following neutrophil activation. Surface expression was recapitulated in a human PLB-985 cell model of neutrophil-like differentiation. Continuous ligation of LILRB3 inhibited key IgA-mediated effector functions, including production of reactive oxygen species, phagocytic uptake, and microbial killing. This suggests that LILRB3 provides an important checkpoint to control human neutrophil activation and their antimicrobial effector functions during resting and early-activation stages of the neutrophil life cycle.


Assuntos
Antígenos CD/metabolismo , Neutrófilos/imunologia , Receptores Fc/metabolismo , Receptores Imunológicos/metabolismo , Infecções Estafilocócicas/imunologia , Antígenos CD/genética , Antígenos CD/isolamento & purificação , Diferenciação Celular/imunologia , Linhagem Celular , Regulação para Baixo/imunologia , Humanos , Ativação de Neutrófilo , Neutrófilos/metabolismo , Fagocitose , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/isolamento & purificação , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus capitis/imunologia
20.
Sci Rep ; 10(1): 1345, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992837

RESUMO

The high incidence of osteomyelitis in vulnerable populations like those with multiple injuries or elderly undergoing joint arthroplasties generates the question what may be their responses to subsequent infection by high virulent isolates. Rabbits were subject to two operations at three week intervals; sham osteomyelitis and sham pyelonephritis (group S); sham osteomyelitis and Escherichia coli pyelonephritis (group P); and Staphylococcus aureus osteomyelitis and E. coli pyelonephritis (group OP). Survival was recorded; cytokine stimulation of circulating mononuclear cells (PBMCs) and tissue myeloperoxidase (MPO) activity and bacterial growth were monitored. In some experiments, dalbavancin treatment was given before pyelonephritis. Healthy PBMCs were pre-treated with bone homogenate, S. aureus or both. Mortality of groups S, P and OP after induction of pyelonephritis was 0%, 50% and 8.3% respectively. Tumour necrosis factor-alpha (TNFα) production by PBMCs was significantly lower in the OP group at 48 hours. E. coli bacterial load was similar in groups P and OP at death or sacrifice whereas the MPO activity of group OP was decreased. Production of TNFα was further decreased among dalbavancin treated rabbits; in these rabbits tissue MPO was increased. TNFα production decreased when healthy PBMCs pre-treated with bone homogenate, S. aureus (HKSA) or both were stimulated with E. coli (HKEC); production was further decreased in the presence of anti-TLR4 and anti-TLR9. It is concluded that staphylococcal osteomyelitis modulated the innate immune responses of the host leading to protection from death by highly virulent E. coli. Tolerance to TLR ligands is the most likely mechanism of action.


Assuntos
Infecções por Escherichia coli/etiologia , Osteomielite/complicações , Pielonefrite/etiologia , Infecções Estafilocócicas/complicações , Staphylococcus aureus/fisiologia , Animais , Modelos Animais de Doenças , Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/mortalidade , Imunidade Inata , Osteomielite/imunologia , Osteomielite/microbiologia , Prognóstico , Pielonefrite/metabolismo , Pielonefrite/mortalidade , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA