Investigating the Role of microRNA in Host–Influenza A and Other Respiratory RNA Virus Interactions

Respiratory RNA viruses extensively reprogram host regulatory networks, thereby influencing viral replication, immune evasion, and disease severity. This review examines microRNAs (miRNAs) as regulatory interfaces in host–virus interactions, focusing on influenza A virus as a paradigmatic model while integrating evidence from other respiratory RNA viruses as SARS-CoV-2 and respiratory syncytial virus. After outlining canonical miRNA biogenesis and its manipulation during infection, we discuss how respiratory RNA viruses converge on shared miRNA-regulated pathways, including interferon and NF-κB signaling, apoptosis, autophagy, cellular metabolism, and redox homeostasis. Within these networks, host miRNAs can directly target viral RNAs and modulate antiviral defenses and inflammation, whereas viruses can reshape miRNA expression to facilitate replication, influencing immunopathology. The possibility that RNA viruses encode authentic miRNAs is also critically evaluated; current evidence indicates that manipulating host miRNA biogenesis machinery and remodeling miRNA networks are more prevalent than producing canonical viral miRNAs. Finally, the potential of circulating miRNAs as diagnostic and prognostic biomarkers is considered, as well as the capability of miRNA mimics and antagomiRs to function as host-directed therapeutic strategies. Their clinical translation, however, will require standardized validation, cell- and time-resolved studies, efficient delivery systems, and a careful assessment of specificity, safety, and context-dependent effects.