An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis

By M. Berry, C. Graham, Finlay W Mcnab, Zhaohui Xu, S. Bloch, T. Oni, K. Wilkinson, R. Banchereau, Jason A. Skinner, R. Wilkinson and 11 more. Nature, 2010

1,829 citations recorded by the source corpus.

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and type I IFN-αβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-αβ signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.

Subfields: Epidemiology, Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/0557f1a0807622767d8e424517b4b344572ea25d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. A. O’Garra
2. F. Sallusto
3. Rafi Ahmed
4. R. Wilkinson
5. A. Mócsai
6. G. Trinchieri
7. K. Araki
8. V. Deretic

In Immunology

1. Rafi Ahmed
2. F. Sallusto
3. A. Lanzavecchia
4. K. Araki
5. G. Trinchieri
6. A. O’Garra
7. D. Mathis
8. Aviv Regev

In Infectious Diseases

1. A. O’Garra
2. Rafi Ahmed
3. R. Wilkinson
4. G. Trinchieri
5. V. Deretic
6. M. Berry
7. Finlay W Mcnab
8. Paul S. Redford

Citations in the corpus

• Diverse novel functions of neutrophils in immunity, inflammation, and beyond (2013, background): “Neutrophils are terminally differentiated cells that develop in the bone marrow where they are also stored for release into the circulation (Borregaard, 2010).”
• From Vaccines to Memory and Back (2010, positive): “This analysis can be combined with global gene profiling that provide specific signatures of immune responses (Berry et al., 2010; Querec et al., 2009).”
• Parsing the interferon transcriptional network and its disease associations (2016, positive): “…in blood cells in many diseases (Theofilopoulos et al., 2005; Forster, 2012), including bacterial or parasitic infections as might be expected (Berry et al., 2010) but also a range of auto-inflammatory disease like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), dermatomyositis,…”
• Autophagy in inflammation, infection, and immunometabolism (2021, background): “, 2014) of relevance in diseases such as tuberculosis (Berry et al., 2010; Novikov et al., 2011).”
• The immune response in tuberculosis. (2013, methodology): “Examination of immune responses using a global systems approach has been a powerful tool for improving our understanding of the molecular heterogeneity of latent and active TB and has revealed a previously unappreciated potential role of type I IFN in the development of active TB in humans (72).”
• Macrophage defense mechanisms against intracellular bacteria (2015, background): “Therefore, it is no surprise that IFN-b transcriptome signatures were found to be associated with active but not latent TB (101).”
• INTERFEROME v2.0: an updated database of annotated interferon-regulated genes (2012, background): “In recent years, the availability of genomics technologies and improvements in analytical methods, such as those made available in the Interferome, has highlighted the association of pathways activated by IFNs in a broad range of diseases, including influenza outbreaks (32), hepatitis (33), HIV (34)”
• Type I interferon: friend or foe? (2010, result): “…from the blood of patients with tuberculosis revealed that the signature was dominated by a neutrophildriven IFN-inducible gene profile, consistent with both type I and type II IFN signaling, suggesting both changes in cellular composition and altered gene expression (Berry et al., 2010).”