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

Lúcia Moreira-Teixeira,Philippa J Stimpson,Sergo Vashakidze,Qian Wang,Paula Rodríguez-Martínez,Jeremy Sousa,Alejandro Suarez-Bonnet,Cristina Vilaplana,Anne O’Garra,Iker Valle Aramburu,Probir Chakravarty,Marianna Ioannou,Venizelos Papayannopoulos,Sabelo Hadebe,Margarida Saraiva,Simon L Priestnall,Evangelos Stavropoulos,Eleanor Herbert,Kaori L Fonseca

doi:10.1038/s41467-020-19412-6

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.

Highlights

Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear
GM-CSF blockade during M. tuberculosis infection resulted in enhanced host susceptibility, similar to the findings reported for GM-CSF-deficient mice[27,31], with significant weight loss (Fig. 1b), increased lung mycobacterial loads (Fig. 1c) and exacerbated lung pathology (Fig. 1d and Supplementary Data 1), when compared to infected Ctrl Ab treated mice
The mechanisms underlying the pathology observed in the absence of GM-CSF signalling during M. tuberculosis infection remain poorly understood, since past studies performed in GM-CSF-deficient mice had confounding lung pathologies[33,34], Fig. 6 IFNAR deletion abrogates disease exacerbation prompted by GM-CSF blockade during infection

Summary

Introduction

Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Impaired innate immune responses and decreased recruitment of protective IFNγ producing CD4+ T cells into the site of infection have been proposed as mechanisms for the increased susceptibility following M. tuberculosis infection in mice deficient in GMCSF27,31 These studies are difficult to interpret owing to the developmental defects in alveolar macrophages and abnormalities in surfactant recycling in mice lacking GM-CSF from birth, leading to the development of a lung disease that resembles human pulmonary alveolar proteinosis (PAP)[33,34]. We show that increased expression of genes associated with neutrophil recruitment and activation, as well as type I IFN-inducible genes, in blood and lungs of M. tuberculosis-infected mice in the absence of GM-CSF signalling, accompanies enhanced mycobacterial growth and lung pathology. Disease exacerbation driven by GM-CSF blockade is neutrophil-dependent and associates with exacerbated neutrophil extracellular trap (NET) formation at the site of infection

Methods

Results

Conclusion