IMMUNOSTIMULATING RNA OF SACCHAROMYCES CEREVISIAE: STRUCTURE, INNATE IMMUNE RECEPTORS AND MOLECULAR MECHANISMS OF ACTION

Innate immunity plays a pivotal role in the early defense against viral infections, and nucleic acid–sensing receptors are one of the key components of this system. High-molecular-weight RNA of the yeast Saccharomyces cerevisiae represents a natural source of ligands for endosomal Toll-like receptors (TLR3, TLR7, TLR8), cytoplasmic RIG-I-like receptors (RIG-I, MDA5), protein kinase R (PKR) and the 2′,5′-oligoadenylate–RNase L system. This review summarizes current data on the structure and physicochemical properties of major classes of yeast RNA (double-stranded L and M RNAs of virus-like particles, single-stranded 20S and 23S replicons, retrovirus-like Ty elements), including their charge, length, polydispersity and secondary structure. We discuss in detail the molecular mechanisms by which these RNAs are recognized by innate immune receptors, with a focus on the TLR3/TRIF, TLR7/8/MyD88, RIG-I/MDA5/MAVS and PKR/2′,5′-oligoadenylate–RNase L signalling pathways. Special attention is paid to the position of high-molecular-weight yeast RNA among interferon-inducing RNA agents. Synthetic polynucleotides (such as poly(I:C)), natural double-stranded RNAs of viral origin (including dsRNA-based antiviral preparations) and yeast RNA-based preparations (single- and dou-ble-stranded Saccharomyces spp. RNA) are compared. Experimental data on the immunobiological effects of high-molecular-weight yeast RNA in in vitro and in vivo models are summarized, including induction of type I interferon, interferon-stimulated genes, modulation of antiviral defense and cellular immune responses. Overall, yeast high-molecular-weight RNA occupies an intermediate position between synthetic polynucleotides and low-molecular-weight interferon inducers in terms of the breadth of the pattern-recognition receptor spectrum and interferonogenic potency, while offering promising opportunities for pharmaceutical optimization and the development of complex medicinal formulations.