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[PMID]: 28468970 [Au] Autor: Chowdhary VR; Krogman A; Tilahun AY; Alexander MP; David CS; Rajagopalan G [Ad] Endereço: Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905. [Ti] Título: Concomitant Disruption of and Genes Facilitates the Development of Double Negative αß TCR Peripheral T Cells That Respond Robustly to Staphylococcal Superantigen. [So] Source: J Immunol;198(11):4413-4424, 2017 06 01. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Mature peripheral double negative T (DNT) cells expressing αß TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated and genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3 αß TCR thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3 αß TCR cells and Foxp3 T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells. [Mh] Termos MeSH primário: Antígenos CD4/genética Antígenos CD4/imunologia Antígenos CD8/genética Antígenos CD8/imunologia Enterotoxinas/imunologia Superantígenos/imunologia Subpopulações de Linfócitos T/imunologia [Mh] Termos MeSH secundário: Animais Antígenos HLA-DQ/genética Antígenos HLA-DQ/imunologia Antígeno HLA-DR3/genética Antígeno HLA-DR3/imunologia Antígenos de Histocompatibilidade Classe II/imunologia Camundongos Camundongos Knockout Camundongos Transgênicos Receptores de Antígenos de Linfócitos T alfa-beta/genética Receptores de Antígenos de Linfócitos T alfa-beta/imunologia Baço/citologia Baço/imunologia Timo/citologia Timo/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (CD4 Antigens); 0 (CD8 Antigens); 0 (Enterotoxins); 0 (HLA-DQ Antigens); 0 (HLA-DQ8 antigen); 0 (HLA-DR3 Antigen); 0 (Histocompatibility Antigens Class II); 0 (Receptors, Antigen, T-Cell, alpha-beta); 0 (Superantigens); 39424-53-8 (enterotoxin B, staphylococcal) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 180127 [Lr] Data última revisão: 180127 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1601991

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[PMID]: 28934339 [Au] Autor: Rudkin JK; McLoughlin RM; Preston A; Massey RC [Ad] Endereço: School of Microbiology, University College Cork, Cork, Ireland. [Ti] Título: Bacterial toxins: Offensive, defensive, or something else altogether? [So] Source: PLoS Pathog;13(9):e1006452, 2017 Sep. [Is] ISSN: 1553-7374 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The secretion of proteins that damage host tissue is well established as integral to the infectious processes of many bacterial pathogens. However, recent advances in our understanding of the activity of toxins suggest that the attributes we have assigned to them from early in vitro experimentation have misled us into thinking of them as merely destructive tools. Here, we will discuss the multifarious ways in which toxins contribute to the lifestyle of bacteria and, by considering their activity from an evolutionary perspective, demonstrate how this extends far beyond their ability to destroy host tissue. [Mh] Termos MeSH primário: Adenilil Ciclases/metabolismo Bactérias/metabolismo Toxinas Bacterianas/metabolismo Evolução Biológica Interações Hospedeiro-Patógeno/imunologia [Mh] Termos MeSH secundário: Animais Toxinas Bacterianas/imunologia Toxinas Bacterianas/toxicidade Seres Humanos Superantígenos/imunologia Superantígenos/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Bacterial Toxins); 0 (Superantigens); EC 4.6.1.1 (Adenylyl Cyclases) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171017 [Lr] Data última revisão: 171017 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170922 [St] Status: MEDLINE [do] DOI: 10.1371/journal.ppat.1006452

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[PMID]: 28880920 [Au] Autor: Tuffs SW; James DBA; Bestebroer J; Richards AC; Goncheva MI; O'Shea M; Wee BA; Seo KS; Schlievert PM; Lengeling A; van Strijp JA; Torres VJ; Fitzgerald JR [Ad] Endereço: The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, Scotland, United States of America. [Ti] Título: The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function. [So] Source: PLoS Pathog;13(9):e1006461, 2017 Sep. [Is] ISSN: 1553-7374 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Bacterial superantigens (SAgs) cause Vß-dependent T-cell proliferation leading to immune dysregulation associated with the pathogenesis of life-threatening infections such as toxic shock syndrome, and necrotizing pneumonia. Previously, we demonstrated that staphylococcal enterotoxin-like toxin X (SElX) from Staphylococcus aureus is a classical superantigen that exhibits T-cell activation in a Vß-specific manner, and contributes to the pathogenesis of necrotizing pneumonia. Here, we discovered that SElX can also bind to neutrophils from human and other mammalian species and disrupt IgG-mediated phagocytosis. Site-directed mutagenesis of the conserved sialic acid-binding motif of SElX abolished neutrophil binding and phagocytic killing, and revealed multiple glycosylated neutrophil receptors for SElX binding. Furthermore, the neutrophil binding-deficient mutant of SElX retained its capacity for T-cell activation demonstrating that SElX exhibits mechanistically independent activities on distinct cell populations associated with acquired and innate immunity, respectively. Finally, we demonstrated that the neutrophil-binding activity rather than superantigenicity is responsible for the SElX-dependent virulence observed in a necrotizing pneumonia rabbit model of infection. Taken together, we report the first example of a SAg, that can manipulate both the innate and adaptive arms of the human immune system during S. aureus pathogenesis. [Mh] Termos MeSH primário: Enterotoxinas/metabolismo Exfoliatinas/farmacologia Neutrófilos/efeitos dos fármacos Infecções Estafilocócicas Superantígenos/farmacologia [Mh] Termos MeSH secundário: Animais Exfoliatinas/metabolismo Seres Humanos Ativação Linfocitária/imunologia Neutrófilos/imunologia Coelhos Receptores de Antígenos de Linfócitos T alfa-beta/imunologia Staphylococcus aureus/química Staphylococcus aureus/metabolismo Superantígenos/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enterotoxins); 0 (Exfoliatins); 0 (Receptors, Antigen, T-Cell, alpha-beta); 0 (Superantigens) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171017 [Lr] Data última revisão: 171017 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170908 [St] Status: MEDLINE [do] DOI: 10.1371/journal.ppat.1006461

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[PMID]: 28880913 [Au] Autor: Langley RJ; Ting YT; Clow F; Young PG; Radcliff FJ; Choi JM; Sequeira RP; Holtfreter S; Baker H; Fraser JD [Ad] Endereço: School of Medical Sciences, and The Maurice Wilkins Centre for Molecular Biodiscovery, the University of Auckland, Auckland, New Zealand. [Ti] Título: Staphylococcal enterotoxin-like X (SElX) is a unique superantigen with functional features of two major families of staphylococcal virulence factors. [So] Source: PLoS Pathog;13(9):e1006549, 2017 Sep. [Is] ISSN: 1553-7374 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Staphylococcus aureus is an opportunistic pathogen that produces many virulence factors. Two major families of which are the staphylococcal superantigens (SAgs) and the Staphylococcal Superantigen-Like (SSL) exoproteins. The former are immunomodulatory toxins that induce a Vß-specific activation of T cells, while the latter are immune evasion molecules that interfere with a wide range of innate immune defences. The superantigenic properties of Staphylococcal enterotoxin-like X (SElX) have recently been established. We now reveal that SElX also possesses functional characteristics of the SSLs. A region of SElX displays high homology to the sialyl-lactosamine (sLacNac)-specific binding site present in a sub-family of SSLs. By analysing the interaction of SElX with sLacNac-containing glycans we show that SElX has an equivalent specificity and host cell binding range to the SSLs. Mutation of key amino acids in this conserved region affects the ability of SElX to bind to cells of myeloid origin and significantly reduces its ability to protect S. aureus from destruction in a whole blood killing (WBK) assay. Like the SSLs, SElX is up-regulated early during infection and is under the control of the S. aureus exotoxin expression (Sae) two component gene regulatory system. Additionally, the structure of SElX in complex with the sLacNac-containing tetrasaccharide sialyl Lewis X (sLeX) reveals that SElX is a unique single-domain SAg. In summary, SElX is an 'SSL-like' SAg. [Mh] Termos MeSH primário: Enterotoxinas/metabolismo Exotoxinas/metabolismo Evasão da Resposta Imune/imunologia Infecções Estafilocócicas/metabolismo Staphylococcus aureus/metabolismo Fatores de Virulência/metabolismo [Mh] Termos MeSH secundário: Animais Células Cultivadas Seres Humanos Camundongos Infecções Estafilocócicas/imunologia Superantígenos/genética Fatores de Virulência/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enterotoxins); 0 (Exotoxins); 0 (Superantigens); 0 (Virulence Factors) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171017 [Lr] Data última revisão: 171017 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170908 [St] Status: MEDLINE [do] DOI: 10.1371/journal.ppat.1006549

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[PMID]: 28847519 [Au] Autor: Rogalski A; Soerensen C; Op den Brouw B; Lister C; Dashevsky D; Arbuckle K; Gloria A; Zdenek CN; Casewell NR; Gutiérrez JM; Wüster W; Ali SA; Masci P; Rowley P; Frank N; Fry BG [Ad] Endereço: Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia QLD 4072 Australia. [Ti] Título: Differential procoagulant effects of saw-scaled viper (Serpentes: Viperidae: Echis) snake venoms on human plasma and the narrow taxonomic ranges of antivenom efficacies. [So] Source: Toxicol Lett;280:159-170, 2017 Oct 05. [Is] ISSN: 1879-3169 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Saw-scaled vipers (genus Echis) are one of the leading causes of snakebite morbidity and mortality in parts of Sub-Saharan Africa, the Middle East, and vast regions of Asia, constituting a public health burden exceeding that of almost any other snake genus globally. Venom-induced consumption coagulopathy, owing to the action of potent procoagulant toxins, is one of the most relevant clinical manifestations of envenomings by Echis spp. Clinical experience and prior studies examining a limited range of venoms and restricted antivenoms have demonstrated for some antivenoms an extreme lack of antivenom cross-reactivity between different species of this genus, sometimes resulting in catastrophic treatment failure. This study undertook the most comprehensive testing of Echis venom effects upon the coagulation of human plasma, and also the broadest examination of antivenom potency and cross-reactivity, to-date. 10 Echis species/populations and four antivenoms (two African, two Asian) were studied. The results indicate that the venoms are, in general, potently procoagulant but that the relative dependence on calcium or phospholipid cofactors is highly variable. Additionally, three out of the four antivenoms tested demonstrated only a very narrow taxonomic range of effectiveness in preventing coagulopathy, with only the SAIMR antivenom displaying significant levels of cross-reactivity. These results were in conflict with previous studies using prolonged preincubation of antivenom with venom to suggest effective cross-reactivity levels for the ICP Echi-Tab antivenom. These findings both inform upon potential clinical effects of envenomation in humans and highlight the extreme limitations of available treatment. It is hoped that this will spur efforts into the development of antivenoms with more comprehensive coverage for bites not only from wild snakes but also from specimens widely kept in zoological collections. [Mh] Termos MeSH primário: Coagulação Sanguínea/efeitos dos fármacos Plasma/fisiologia Venenos de Víboras/toxicidade Viperidae [Mh] Termos MeSH secundário: Animais Proteínas de Bactérias Exotoxinas Seres Humanos Superantígenos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (Exotoxins); 0 (SpeJ protein, Streptococcus pyogenes); 0 (Superantigens); 0 (Viper Venoms) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171017 [Lr] Data última revisão: 171017 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170830 [St] Status: MEDLINE

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[PMID]: 28719668 [Au] Autor: Imöhl M; Fitzner C; Perniciaro S; van der Linden M [Ad] Endereço: Institute of Medical Microbiology and National Reference Center for Streptococci, University Hospital (RWTH), Aachen, Germany. [Ti] Título: Epidemiology and distribution of 10 superantigens among invasive Streptococcus pyogenes disease in Germany from 2009 to 2014. [So] Source: PLoS One;12(7):e0180757, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A nationwide laboratory-based surveillance study of invasive S. pyogenes infections was conducted in Germany. Invasive isolates (n = 719) were obtained between 2009 and 2014. Most isolates were obtained from blood (92.1%). The proportions of isolates from cerebrospinal fluid, pleural fluid, synovial fluid and peritoneal fluid were 3.9%, 1.8%, 1.7% and 0.6%, respectively. The most common emm types were emm 1 (31.8%), emm 28 (15.4%) and emm 89 (14.5%). The most common superantigen genes (speA, speC, speG, speH, speI, speJ, speK, speL, speM, ssa) identified from S. pyogenes were speG (92.1%), speJ (50.9%), and speC (42.0%). Significant associations of superantigen genes with underlying conditions or risks were observed in speG, speH, speJ, and speK. Significant associations between emm types or superantigen genes with clinical complications were observed in emm type 3 and in superantigen gene speA 1-3. Most frequent clinical manifestations included sepsis 59.4%, STSS 6.3%, meningitis 5.4%, and necrotizing fasciitis 5.0% (significantly associated with emm1). [Mh] Termos MeSH primário: Infecções Estreptocócicas/epidemiologia Streptococcus pyogenes/imunologia Streptococcus pyogenes/fisiologia Superantígenos/análise [Mh] Termos MeSH secundário: Adolescente Adulto Idoso Idoso de 80 Anos ou mais Criança Pré-Escolar Feminino Alemanha/epidemiologia Seres Humanos Lactente Recém-Nascido Masculino Meia-Idade Fatores de Risco Infecções Estreptocócicas/complicações Infecções Estreptocócicas/diagnóstico Superantígenos/imunologia Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Superantigens) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170927 [Lr] Data última revisão: 170927 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170719 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0180757

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[PMID]: 28715277 [Au] Autor: Liu T; Li L; Yin L; Yu H; Jing H; Liu Y; Kong C; Xu M [Ad] Endereço: a Department of Urology , The First Affiliated Hospital of China Medical University , Shenyang , People's Republic of China. [Ti] Título: Superantigen staphylococcal enterotoxin C1 inhibits the growth of bladder cancer. [So] Source: Biosci Biotechnol Biochem;81(9):1741-1746, 2017 Sep. [Is] ISSN: 1347-6947 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Superantigens can induce cell-mediated cytotoxicity preferentially against MHC II-positive target cells with large amounts of inflammatory cytokines releasing. In this study, superantigen staphylococcal enterotoxin C (SEC) 1 was investigated to evaluate its potential in bladder cancer immunotherapy in vitro and in vivo. Our results revealed that SEC1 could stimulate the proliferation of human peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner, accompanied with the release of interleukin-2, interferon-γ, and tumor necrosis factor-α, and increased the population of CD4 T cells and CD8 T cells. PBMCs stimulated by SEC1 could initiate significant cytotoxicity towards human bladder cancer cells in vitro. The results of in vivo antitumor experiment indicated that SEC1 could decrease the rate of tumor formation and prolong the survival time of tumor-bearing mice. Our study demonstrated that SEC1 inhibited the growth of bladder cancer. And it is also suggested that SEC1 may become a candidate for bladder cancer immunotherapy. [Mh] Termos MeSH primário: Enterotoxinas/farmacologia Superantígenos/farmacologia Neoplasias da Bexiga Urinária/patologia [Mh] Termos MeSH secundário: Animais Linfócitos T CD4-Positivos/citologia Linfócitos T CD4-Positivos/efeitos dos fármacos Linfócitos T CD8-Positivos/citologia Linfócitos T CD8-Positivos/efeitos dos fármacos Contagem de Células Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Feminino Interferon gama/secreção Interleucina-2/secreção Camundongos Fator de Necrose Tumoral alfa/secreção [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enterotoxins); 0 (Interleukin-2); 0 (Superantigens); 0 (Tumor Necrosis Factor-alpha); 39424-54-9 (enterotoxin C, staphylococcal); 82115-62-6 (Interferon-gamma) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170718 [St] Status: MEDLINE [do] DOI: 10.1080/09168451.2017.1350564

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[PMID]: 28683848 [Au] Autor: Cheng KJ; Xu YY; Zhou ML; Zhou SH; Wang SQ [Ad] Endereço: Department of Otolaryngology,First Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou,China. [Ti] Título: Role of local allergic inflammation and Staphylococcus aureus enterotoxins in Chinese patients with chronic rhinosinusitis with nasal polyps. [So] Source: J Laryngol Otol;131(8):707-713, 2017 Aug. [Is] ISSN: 1748-5460 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: To investigate the role of local allergic inflammation and Staphylococcus aureus enterotoxins in chronic rhinosinusitis with nasal polyps. METHODS: This study included 36 patients with chronic rhinosinusitis with nasal polyps and 18 controls. Total immunoglobulin E, eosinophil cationic protein, staphylococcal enterotoxin types A and B specific immunoglobulin E, staphylococcal enterotoxin types A and B, and myeloperoxidase levels were determined. RESULTS: Four patients with chronic rhinosinusitis with nasal polyps had a local allergy. All chronic rhinosinusitis with nasal polyps patients tested negative for staphylococcal enterotoxin types A and B specific immunoglobulin E. The chronic rhinosinusitis with nasal polyps group had significantly elevated staphylococcal enterotoxin types A and B levels in the supernatant. Fourteen patients belonged to the eosinophilic chronic rhinosinusitis with nasal polyps group and the others were characterised as having non-eosinophilic chronic rhinosinusitis with nasal polyps. CONCLUSION: Local allergy may play a role in chronic rhinosinusitis with nasal polyps, independent of staphylococcal enterotoxin superantigens. Staphylococcal enterotoxins may be important in the pathogenesis of chronic rhinosinusitis with nasal polyps; however, their roles as superantigens were not confirmed in this study. In Chinese subjects, chronic rhinosinusitis with nasal polyps usually manifests as a neutrophilic inflammation. [Mh] Termos MeSH primário: Enterotoxinas/sangue Hipersensibilidade/imunologia Pólipos Nasais/imunologia Rinite/imunologia Sinusite/imunologia Staphylococcus aureus/imunologia [Mh] Termos MeSH secundário: Adulto Estudos de Casos e Controles China Doença Crônica Enterotoxinas/imunologia Proteína Catiônica de Eosinófilo/sangue Feminino Seres Humanos Hipersensibilidade/sangue Hipersensibilidade/microbiologia Imunoglobulina E/sangue Imunoglobulina E/imunologia Masculino Meia-Idade Pólipos Nasais/sangue Pólipos Nasais/microbiologia Peroxidase/sangue Rinite/sangue Rinite/microbiologia Sinusite/sangue Sinusite/microbiologia Superantígenos/sangue Superantígenos/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Enterotoxins); 0 (Superantigens); 37337-57-8 (enterotoxin A, Staphylococcal); 37341-29-0 (Immunoglobulin E); 39424-53-8 (enterotoxin B, staphylococcal); EC 1.11.1.7 (Peroxidase); EC 3.1.27.- (Eosinophil Cationic Protein) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170831 [Lr] Data última revisão: 170831 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170708 [St] Status: MEDLINE [do] DOI: 10.1017/S0022215117001335

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[PMID]: 28632753 [Au] Autor: Shaler CR; Choi J; Rudak PT; Memarnejadian A; Szabo PA; Tun-Abraham ME; Rossjohn J; Corbett AJ; McCluskey J; McCormick JK; Lantz O; Hernandez-Alejandro R; Haeryfar SMM [Ad] Endereço: Department of Microbiology and Immunology, Western University, London, Ontario, Canada. [Ti] Título: MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression. [So] Source: PLoS Biol;15(6):e2001930, 2017 Jun. [Is] ISSN: 1545-7885 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vß-specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses. [Mh] Termos MeSH primário: Antígenos de Bactérias/toxicidade Anergia Clonal Modelos Imunológicos Células T Invariáveis Associadas à Mucosa/imunologia Staphylococcus aureus/imunologia Streptococcus pyogenes/imunologia Superantígenos/toxicidade [Mh] Termos MeSH secundário: Animais Antígenos de Bactérias/metabolismo Células da Medula Óssea/citologia Células da Medula Óssea/efeitos dos fármacos Células da Medula Óssea/imunologia Células da Medula Óssea/metabolismo Linhagem Celular Células Cultivadas Anergia Clonal/efeitos dos fármacos Cruzamentos Genéticos Enterotoxinas/secreção Enterotoxinas/toxicidade Feminino Seres Humanos Hibridomas Imunidade Inata Leucócitos Mononucleares/citologia Leucócitos Mononucleares/efeitos dos fármacos Leucócitos Mononucleares/imunologia Leucócitos Mononucleares/metabolismo Ativação Linfocitária/efeitos dos fármacos Camundongos Camundongos Endogâmicos NOD Camundongos Knockout Camundongos SCID Camundongos Transgênicos Células T Invariáveis Associadas à Mucosa/citologia Células T Invariáveis Associadas à Mucosa/efeitos dos fármacos Células T Invariáveis Associadas à Mucosa/metabolismo Organismos Livres de Patógenos Específicos Staphylococcus aureus/metabolismo Streptococcus pyogenes/metabolismo Superantígenos/metabolismo Quimeras de Transplante/sangue Quimeras de Transplante/imunologia Quimeras de Transplante/metabolismo [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Bacterial); 0 (Enterotoxins); 0 (Superantigens); 39424-53-8 (enterotoxin B, staphylococcal) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170621 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pbio.2001930

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[PMID]: 28582663 [Au] Autor: Umeda K; Nakamura H; Yamamoto K; Nishina N; Yasufuku K; Hirai Y; Hirayama T; Goto K; Hase A; Ogasawara J [Ad] Endereço: Division of Microbiology, Osaka Institute of Public Health, 8-34, Tojo-cho, Tennoji-ku, Osaka 543-0026, Japan. Electronic address: kaor-umeda@iph.osaka.jp. [Ti] Título: Molecular and epidemiological characterization of staphylococcal foodborne outbreak of Staphylococcus aureus harboring seg, sei, sem, sen, seo, and selu genes without production of classical enterotoxins. [So] Source: Int J Food Microbiol;256:30-35, 2017 Sep 01. [Is] ISSN: 1879-3460 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Staphylococcal food poisoning is the result of consumption of food contaminated with staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus. To date, 23 SEs and SE-like enterotoxins (SEls) have been described in the literature. They are divided into classical SEs (SEA-SEE) and new SE/SEls (SEG-SElX). Some have proved to be foodborne-inducible, but others remain unidentified. In May 2016, at an elderly group home in Osaka city, Japan, an outbreak from foodborne pathogens occurred among lunch party participants. Within 2h 30min to 4h 40min, 15 of 53 participants presented gastrointestinal symptoms of vomiting, diarrhea, and nausea. A subsequent laboratory investigation detected S. aureus from most stool samples from patients, several left-over food items, a kitchen swab, and hand swabs from two food handlers. Classical SEs was not detected from S. aureus isolates or left-over food items. From examination for the presence of SE/SEl genes of 20 kinds by PCR, seg, sei, sem, sen, seo, and selu genes were detected in almost all isolates. These isolates exhibited identical or closely related types by coagulase type (type VII), Sma I digested pulsed-field gel electrophoresis analysis and multi-locus sequence typing (MLST-CC45 lineage). These results suggest that the foodborne outbreak was caused by S. aureus harboring seg, sei, sem, sen, seo, and selu genes without production of classical SEs. Additionally, some S. aureus isolates from human nasal swabs and healthy human feces harboring seg, sei, sem, sen, seo, and selu genes without production of classical SEs were classified into CC45 lineage using MLST. These findings suggest new SE/SEls as a potential cause of foodborne outbreaks. [Mh] Termos MeSH primário: Surtos de Doenças Enterotoxinas/genética Intoxicação Alimentar Estafilocócica/epidemiologia Staphylococcus aureus/genética Staphylococcus aureus/isolamento & purificação [Mh] Termos MeSH secundário: Primers do DNA Eletroforese em Gel de Campo Pulsado Enterotoxinas/biossíntese Seres Humanos Japão/epidemiologia Tipagem de Sequências Multilocus Reação em Cadeia da Polimerase/métodos Intoxicação Alimentar Estafilocócica/microbiologia Infecções Estafilocócicas/microbiologia Superantígenos/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA Primers); 0 (Enterotoxins); 0 (Superantigens); 0 (enterotoxin G, staphylococcal); 0 (enterotoxin I, staphylococcal) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170606 [St] Status: MEDLINE

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