Abstract
Tuberculosis (TB) remains a significant human health issue. More effective biomarkers for use in tuberculosis prevention, diagnosis, and treatment, including markers that can discriminate between healthy individuals and those with latent infection, are urgently needed. To identify a set of such markers, we used Solexa sequencing to examine microRNA expression in the serum of patients with active disease, healthy individuals with latent TB, and those with or without prior BCG inoculation. We identified 24 microRNAs that are up-regulated (2.85–1285.93 fold) and 6 microRNAs that are down-regulated (0.003–0.11 fold) (P<0.05) in patients with active TB relative to the three groups of healthy controls. In addition, 75 microRNAs were up-regulated (2.05–2454.58 fold) and 11 were down-regulated (0.001–0.42 fold) (P<0.05) in latent-TB infected individuals relative to BCG- inoculated individuals. Of interest, 134 microRNAs were differentially-expressed in BCG-inoculated relative to un-inoculated individuals (18 up-regulated 2.9–499.29 fold, 116 down-regulated 0.0002–0.5 fold), providing insights into the effects of BCG inoculation at the microRNA level. Target prediction of differentially-expressed microRNAs by microRNA-Gene Network analysis and analysis of pathways affected suggest that regulation of the host immune system by microRNAs is likely to be one of the main factors in the pathogenesis of tuberculosis. qRT-PCR validation indicated that hsa-miR-196b and hsa-miR-376c have potential as markers for active TB disease. The microRNA differential-expression profiles generated in this study provide a good foundation for the development of markers for TB diagnosis, and for investigations on the role of microRNAs in BCG-inoculated and latent-infected individuals.
Highlights
Tuberculosis (TB) remains a significant human health issue
QuantiFERON tests, interferon gamma release assays (IGRAs) that test for a positive immune response to M. tuberculosis, are not affected by BCG inoculation status, they cannot distinguish between latent TB and active disease
A total of 904 microRNAs were obtained, 162 of which showed significantly altered expression in the active TB group compared with the three control groups (LTBI, and healthy BCG-inoculated, and uninoculated individuals) (Figure 1)
Summary
It is estimated that up to two billion individuals throughout the world are currently infected with Mycobacterium tuberculosis (M.tb), 10% of whom will develop active disease during their lifetime [1]. QuantiFERON tests, interferon gamma release assays (IGRAs) that test for a positive immune response to M. tuberculosis, are not affected by BCG inoculation status, they cannot distinguish between latent TB and active disease. MicroRNAs, a class of small non-coding RNAs approximately 21 nucleotides in length that are found in various organisms [4], are more stable than mRNAs and are good candidates for use as biomarkers [5] They modulate gene function at the post-transcriptional level and act in fine tuning various processes such as development, proliferation, cell signaling, and apoptosis
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