Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole-genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (α/β) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (α/β) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient’s blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection.

TB or Not TB: That Is No Longer the Question

“…Although there is an increasing number of molecular signatures or biomarkers for progression of latent TB to active disease (141,143), which are really correlates of pathogenesis, there is at present no established molecular signature for protection against infection or disease. We believe that in the absence of molecular signatures for the dynamic states of the infection that enable prediction of the course of disease and effects of interventions on correlates of protection, it may be necessary to think about developing a safe live infection challenge model that could be used in small-scale studies to measure ability to kill the pathogen (186).…”

“…The most marked characteristic of the "signature" for active TB thus far is the increase in a set of genes regulated by IFNs, in particular the type I IFNs, IFN-b and IFN-a (141,143), although the IFNs themselves were not detected by the microarray. The induction of the type I IFN gene program was associated with the extent of disease (141) and resolved within 2 months of treatment (144).…”

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

“…Transcriptional profiling of blood cells has emerged as a powerful platform for discovery of potential TB biomarkers discriminating patients with TB from healthy uninfected and/or individuals with latent Mtb infection (19)(20)(21)(22)(23)(24). We previously defined a 16-gene blood transcriptional correlate of risk (COR) signature that predicts risk of progression to TB in HIV-negative South African adolescents with Mtb infection and HHCs from South Africa and the Gambia (25).…”

Quest for Correlates of Protection against Tuberculosis

“…TB disease itself is associated with an inflammatory transcriptional blood signature absent in healthy or most latently infected individuals (95)(96)(97)(98)(99)(100)(101). There are several challenging issues in identifying the true correlates of protection against TB, including the lack of good human challenge models and lack of characterization of immune protective cells for ex vivo measurements.…”