RESUMO
Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.
Assuntos
Armadilhas Extracelulares/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interferon Tipo I/metabolismo , Pulmão/microbiologia , Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Pneumonia/imunologia , Tuberculose Pulmonar/imunologia , Animais , Bases de Dados Genéticas , Progressão da Doença , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Interferon Tipo I/genética , Interferon gama/genética , Interferon gama/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/patogenicidade , Pneumonia/genética , Pneumonia/metabolismo , Pneumonia/patologia , RNA-Seq , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologiaRESUMO
The British Journal of Hospital Medicine is 50 years old. This article takes a look back at articles published during the year of its inception from the British Medical Journal, the Lancet and the Journal of the American Medical Association.