An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Abstract

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified 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 following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated 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 IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN 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 under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, 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.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…Whole genome transcriptional analysis of purified cells constitutes a powerful, unbiased strategy for studying cellular immune responses to infection [35]. To the best of our knowledge, this is the first study to conduct a comprehensive assessment of the transcriptional response of purified CD4 1 T cells during bloodstage Plasmodium infection.…”

Refinement of the genetics of the host response to Salmonella infection in MOLF/Ei: regulation of type 1 IFN and TRP3 pathways by Ity2

“…4 In addition, a correlation between the increase in blood type 1 IFN-inducible transcripts and disease severity has been recently reported in patients with active tuberculosis supporting an important role for type 1 IFN in the pathogenesis of intracellular bacterial infections in mouse models of human diseases and in humans. 30 Finally, the third cluster showing transcriptional dysregulation in B6.MOLF-Ity/Ity2.RecD involves the TRP53 pathway (Supplementary Figure S2). Trp53 is a tumor suppressor gene known to balance cell survival and death in response to a variety of intrinsic and extrinsic stress signals.…”

Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis

“…21 MAFB was reported to be highly expressed in active TB compared with lower expression in latent TB in an extensive study of whole-blood gene expression signatures that differentiated active TB cases from health individuals. 22 These variants might influence the development of TB through an effect on the reactive response to M. tuberculosis infection by expression of MAFB from non-lymphocytic population of white cells. Other loci with lower association evidence (P 4M-H o10 À5 ) need additional replication evidence in other populations.…”