Research in context
Evidence before this study
We searched the PubMed database for studies published before July 1, 2015, using the search criteria “tuberculosis AND risk AND blood AND (RNA OR microarray OR transcriptome OR RNA-Seq)”. The resulting scientific literature included several substantial analyses comparing the blood RNA profiles of individuals with active tuberculosis disease and healthy individuals. These important studies have established that the tuberculosis disease state is reflected in the blood RNA profile of the patient with tuberculosis with ongoing disease. The resulting literature also included several small studies reporting candidate host markers for tuberculosis disease risk that have not been rigorously assessed in independent cohorts. Repeating the search without the “(RNA OR microarray OR transcriptome OR RNA-Seq)” term yielded literature with established risk factors for tuberculosis disease, which have been summarised in several reviews. Despite these important studies and known tuberculosis risk factors, it is not possible to predict which individuals infected with Mycobacterium tuberculosis will develop active tuberculosis with tools.
Added value of this study
Our study expands the previous findings by being the first large-scale search for prospective correlates of risk of tuberculosis in healthy individuals before the onset of disease. We used unbiased high-throughput screening of host blood RNA profiles to identify new signatures of risk for tuberculosis. These signatures were confirmed in the original cohort with targeted assays; these targeted assays were then successfully used to predict tuberculosis disease progression in two independent cohorts. Further meta-analyses of published datasets showed that the prognostic signatures might simultaneously serve as diagnostic signatures for tuberculosis.
Implications of all the evidence
Our study provides the first demonstration that host blood RNA signatures can be used to predict progression to active tuberculosis disease in healthy individuals that are latently infected with or exposed to the M tuberculosis pathogen. These findings will result in further follow-up studies to assess whether the prognostic signatures can be used to prevent tuberculosis disease through targeted prophylactic treatment. Additional follow-up studies might focus on optimising the practical measurement of the signatures and understanding the biological significance of the host genes implicated by the signatures.