Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosisMore about Open Access at the Crick
Authors listLucia Moreira-Teixeira Philippa J Stimpson Evangelos Stavropoulos Sabelo Hadebe Probir Chakravarty Marianna Ioannou Iker Valle Aramburu Eleanor Herbert Simon L Priestnall Alejandro Suarez-Bonnet Jeremy Sousa Kaori L Fonseca Qian Wang Sergo Vashakidze Paula Rodríguez-Martínez Cristina Vilaplana Margarida Saraiva Venizelos Papagiannopoulos Anne O'Garra
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.
Journal Nature Communications
Issue number 1