The Francis Crick Institute
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Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis.

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journal contribution
posted on 2020-11-06, 11:16 authored by Lúcia 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 Papayannopoulos, 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.


Crick (Grant ID: 10129, Grant title: Papayannopoulos FC001129) Crick (Grant ID: 10126, Grant title: O' Garra FC001126) Crick (Grant ID: 10009, Grant title: Nye FC001999) Crick (Grant ID: 10002, Grant title: Stewart FC001999)