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.
Highlights
One third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis (TB), which is responsible for about 8–10 million active new cases of TB each year [1,2]
To identify molecular signatures involved in active TB, we applied microarray analysis to compare global gene expression in 23 patients with active TB (t = 0 weeks), whilst they were undergoing treatment (t = 8 weeks), and after they had completed the entire course of treatment (t = 28 weeks)
The same microarray analysis was applied to 23 matched healthy controls from the same population from the same area
Summary
One third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis (TB), which is responsible for about 8–10 million active new cases of TB each year [1,2]. Effective treatment of active TB is crucial in containing spread of the disease, and better diagnostics would greatly impact on TB control by facilitating early treatment. Little is known about the precise mechanisms and pathways that control protective versus pathogenic immunity during TB [3,4]. The IL-12/IFN-c and the TNF/TNFR axis are both crucial in protection during M.tb infection, as genetic STAT1 axis) or acquired (HIV; immune-suppressants; anticytokine auto-antibodies) defects strongly increase host-susceptibility to mycobacterial disease [5,6,7]. IFN-c is produced mostly by CD4+ T cells and assists macrophages in controlling intracellular M.tb infection through various anti-microbial immunity pathways, which include phagosomal maturation; anti-microbial peptides; oxidative stress; apoptosis and autophagy [8]. IFN-c is essential to protection against M.tb, it is not in itself a correlate of protection,
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