Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

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 and Anne O’Garra
Additional contact information
Lúcia Moreira-Teixeira: The Francis Crick Institute
Philippa J. Stimpson: The Francis Crick Institute
Evangelos Stavropoulos: The Francis Crick Institute
Sabelo Hadebe: The Francis Crick Institute
Probir Chakravarty: The Francis Crick Institute
Marianna Ioannou: The Francis Crick Institute
Iker Valle Aramburu: The Francis Crick Institute
Eleanor Herbert: Royal Veterinary College
Simon L. Priestnall: Royal Veterinary College
Alejandro Suarez-Bonnet: Royal Veterinary College
Jeremy Sousa: Universidade do Porto
Kaori L. Fonseca: Universidade do Porto
Qian Wang: The Francis Crick Institute
Sergo Vashakidze: National Center for Tuberculosis and Lung Diseases (NCTLD)
Paula Rodríguez-Martínez: Universitat Autònoma de Barcelona (UAB)
Cristina Vilaplana: Universitat Autònoma de Barcelona (UAB), CIBER Enfermedades Respiratorias. Edifici Laboratoris de Recerca. Can Ruti Campus
Margarida Saraiva: Universidade do Porto
Venizelos Papayannopoulos: The Francis Crick Institute
Anne O’Garra: The Francis Crick Institute

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19412-6

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