Making Sense from Structure: What the Immune System Sees in Viral RNA

Viral RNA structure plays a critical regulatory role in viral replication, serving as a dual-purpose mechanism for encoding genetic information and controlling biological processes. However, these structural elements also serve as pathogen-associated molecular patterns (PAMPs), which are recognized by pattern recognition receptors (PRRs) of the host innate immune system. This review discusses the complex and poorly understood relationship between viral RNA structure and recognition of RNA by PRRs, specifically focusing on Toll-like receptor 3 (TLR3) and Retinoic acid-inducible gene I (RIG-I). While current interaction models rely upon data generated from use of synthetic ligands such as poly(I:C) or perfectly base-paired double-stranded RNA stems, this review highlights significant gaps in our understanding of how PRRs recognize naturally occurring viral RNAs that fold into highly complex three-dimensional structures. Furthermore, we explore how viral evolution and nucleotide variations, such as those observed in influenza viruses, can drastically alter local and distal RNA structure, potentially impacting immune detection. We conclude that moving beyond synthetic models to understand natural RNA structural dynamics is essential for elucidating the mechanisms of viral immune evasion and pathogenesis.