MicroRNAs Come of Age in Diagnostics

Our lead science article in this issue by Xi et al. (2015), MicroRNA-223 is up-regulated in active tuberculosis patients and inhibits apoptosis of macrophages by targeting FOXO3, hits on three of the most important themes we are currently promoting for our journal, Genetic Testing and Molecular Biomarkers. First, it provides a mechanistic understanding of how a potential diagnostic marker works, thus providing a reasonable level of confidence that the proposed diagnostic will achieve high fidelity on clinical application. Second, it integrates human genetics with infectious disease, in this case through the characterization of an interkingdom signaling process. It is hoped that in the future this observation will trigger human genetic variation studies, leading to the determination of whether there are human susceptibility alleles at this locus that modify an individual's risk of either developing clinical tuberculosis or affecting the severity of disease. Such studies are an important topic area that we recently highlighted and for which we put out a call for articles (Ehrlich, 2015). Finally, the focus of the article is on a very timely topic, small RNAs and their role in gene regulation.

Small noncoding RNAs, other than transfer RNAs, have been known for decades ever since the pioneering work of the Steitz laboratory (Lerner et al. 1980), who showed their involvement in eukaryotic mRNA splicing. However, it was the work of Mello and Fire demonstrating that silencing RNAs (siRNAs) function to cleave mRNAs as part of a post-transcriptional process that lead to the recent explosion in the field (Fire et al. 1998). The very rapid awarding of the Nobel Prize in Physiology and Medicine in 2006 for their work emphasized to the molecular biology public the profound transformation that was being wrought based on these discoveries. siRNAs always silence gene function, but they are not the only type of microRNAs involved in regulation of gene expression; other classes of microRNAs may up- or downregulate the expression of various genes (Vaudevan and Steitz, 2007).

In the study by Xi et al. (2015), miR-223 acts to downregulate expression of the FOXO3 gene as a mechanism to prevent apoptosis of Mycobacterium tuberculosis (TB)-infected human macrophages, thereby ensuring the survival of the infecting bacteria. The authors demonstrated that overexpression of the FOXO3 gene mRNA could counteract this inhibitory affect, permitting the macrophages to enter into programmed cell death. Thus, TB's pathogenesis, in part, is through interference with the triggering of a host defense process, a common type of virulence trait among pathogenic bacteria.