Circulating microRNAs as Potential Biomarkers of Infectious Disease

Abstract

microRNAs (miRNAs) are a class of small non-coding endogenous RNA molecules that regulate a wide range of biological processes by post-transcriptionally regulating gene expression. Thousands of these molecules have been discovered to date, and multiple miRNAs have been shown to coordinately fine-tune cellular processes key to organismal development, homeostasis, neurobiology, immunobiology, and control of infection. The fundamental regulatory role of miRNAs in a variety of biological processes suggests that differential expression of these transcripts may be exploited as a novel source of molecular biomarkers for many different disease pathologies or abnormalities. This has been emphasized by the recent discovery of remarkably stable miRNAs in mammalian biofluids, which may originate from intracellular processes elsewhere in the body. The potential of circulating miRNAs as biomarkers of disease has mainly been demonstrated for various types of cancer. More recently, however, attention has focused on the use of circulating miRNAs as diagnostic/prognostic biomarkers of infectious disease; for example, human tuberculosis caused by infection with Mycobacterium tuberculosis, sepsis caused by multiple infectious agents, and viral hepatitis. Here, we review these developments and discuss prospects and challenges for translating circulating miRNA into novel diagnostics for infectious disease.

Keywords: biomarker; diagnostic; infection; microRNA; plasma; serum; transcriptomics.

Figure 1

A tuberculosis lung granuloma demonstrates how specific circulating microRNAs (miRNAs) may arise during an infection process. Mycobacterial pathogen-associated molecular patterns are recognized by toll-like receptors (TLRs) and other pattern recognition receptors, which result in the upregulation of primary-miRNAs in macrophages. These transcripts are subsequently cleaved in the nucleus and cytoplasm by Drosha and Dicer, respectively, resulting in 21–25 nucleotide mature miRNAs that act to fine-tune intracellular immune processes. Specific pathways and components of the immune response may be regulated by different miRNA subsets. Concurrently, the surrounding T lymphocytes involved in granuloma formation/maintenance upregulate T cell subset-specific miRNAs as a means of modulating the type of adaptive immune response. Mature miRNAs generated in macrophages and T cells may also be released into the extracellular environment within exosomes, heterogeneous microvesicles, or in association with high-density lipoprotein, LDL, or other protein complexes. Subsequently, by means not yet fully understood, these extracellular miRNAs move from local sites of infection to the circulatory system. This process can therefore give rise to infection-specific circulating miRNA expression signatures that can readily be accessed from multiple biological fluids (e.g., serum, plasma, or sputum).