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1.
Nat Commun ; 7: 13696, 2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-27982078

RESUMO

Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support TH2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG1 and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.


Assuntos
Asma/induzido quimicamente , Asma/metabolismo , Mastócitos/fisiologia , Receptores de IgE/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Remodelação das Vias Aéreas , Animais , Anticorpos , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/toxicidade , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Imunoglobulina E , Imunoglobulina G , Camundongos , Camundongos Knockout , Ovalbumina/imunologia , Ovalbumina/toxicidade , Receptores de IgE/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética
2.
Proc Natl Acad Sci U S A ; 112(46): 14337-42, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26489655

RESUMO

Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus α-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7(-/-) mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.


Assuntos
Junções Aderentes/metabolismo , Toxinas Bacterianas/metabolismo , Proteínas Hemolisinas/metabolismo , Staphylococcus aureus Resistente à Meticilina/metabolismo , Infecções Estafilocócicas/metabolismo , Vasculite/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAM10 , Junções Aderentes/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Toxinas Bacterianas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteínas Hemolisinas/genética , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Knockout , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/patologia , Vasculite/genética , Vasculite/microbiologia , Vasculite/patologia
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