RESUMEN
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.
Asunto(s)
Trampas Extracelulares/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interferón Tipo I/metabolismo , Pulmón/microbiología , Mycobacterium tuberculosis/inmunología , Neutrófilos/inmunología , Neumonía/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Bases de Datos Genéticas , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Interferón Tipo I/genética , Interferón gamma/genética , Interferón gamma/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium tuberculosis/patogenicidad , Neumonía/genética , Neumonía/metabolismo , Neumonía/patología , RNA-Seq , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/microbiologíaRESUMEN
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.