MicroRNAs in Ocular Infection

Abstract

MicroRNAs (miRNAs) are small, non-coding, regulatory RNA molecules and constitute a newly recognized, important layer of gene-expression regulation at post-transcriptional levels. miRNAs quantitatively fine tune the expression of their downstream genes in a cell type- and developmental stage-specific fashion. miRNAs have been proven to play important roles in the normal development and function as well as in the pathogenesis of diseases in all tissues and organ systems. miRNAs have emerged as new therapeutic targets and biomarkers for treatment and diagnosis of various diseases. Although miRNA research in ocular infection remains in its early stages, a handful of pioneering studies have provided insight into the roles of miRNAs in the pathogenesis of parasitic, fungal, bacterial, and viral ocular infections. Here, we review the current status of research in miRNAs in several major ocular infectious diseases. We predict that the field of miRNAs in ocular infection will greatly expand with the discovery of novel miRNA-involved molecular mechanisms that will inform development of new therapies and identify novel diagnostic biomarkers.

Keywords: bacterial keratitis; fungal keratitis; herpes simplex stromal keratitis (HSK); microRNAs (miRNAs), ocular infection; pseudomonas aeruginosa (PA); river blindness; trachoma.

Figure 1

miRNA biogenesis and functions. In the nucleus, the primary transcript of miRNA, referred as pri-miRNA, is mostly transcribed by RNA polymerase II (A). More than 25% of the conserved and >50% of the poorly conserved miRNAs are derived from introns of protein-coding genes (B). The pri-miRNAs fold into hair-pin structures, which are cleaved by an RNase III endonuclease, Drosha in the Drosha-DGCR8 complex, to form 60–70 nt stem loop intermediates, known as pre-miRNAs, with a 2-nt 3′ overhang (C). Pre-miRNAs are transported to the cytoplasm by Ran-GTP and an export receptor, Exportin 5 (D). In the cytosol, pre-miRNAs are cleaved by another RNase III endonuclease, Dicer in the Dicer/TRBP complex, to form ~22-bp miRNA duplexes with a 2-nt 3′ overhang (E,F). TRBP recruits Agonaute protein Ago2 and other Ago proteins to initiate the assembly of the RNA-induced silencing complex (RISC). One strand of the duplex becomes mature miRNA and is incorporated in the RISC complex (G); the other strand, miRNA*, is degraded by small RNA degrading nuclease (SDN) (in Arabidopsis) and 5′-3′ exonuclease 2 homolog (XRN2) in Caenorhabditis elegans (H). Mature miRNAs base pair with their target mRNAs in the 3′ UTR (I,J). When the miRNA and the target sites have perfect or nearly perfect complementarity, miRNAs direct cleavage of the target mRNAs by Ago2 (I); when the base-pairing is imperfect, miRNA with the RISC can destabilize the mRNA by deadenylation and subsequent decapping, and repress translation of the targeted mRNA by blocking translation initiation and/or inhibiting elongation (J). (Modified from Xu, 2009 [6]). Muture miRNA can be also degraded through target RNA-directed miRNA degradation (TDMD) (K).