Non-coding RNAs, the vast majority of the human transcriptome that is never translated into protein, have emerged as central regulators of how the innate immune system responds to respiratory viruses such as influenza A virus and SARS-CoV-2. In a review published in Discover Immunity, researchers Kushal Ramrao Junghare, Shrinkhla Singh, Madhavan Parthasarathy and Himanshu Kumar synthesise evidence showing that these RNA molecules fine-tune the expression of key signalling proteins, transcription factors and cytokines, and can either strengthen or weaken antiviral defences depending on the cellular context.
The innate immune system provides the first line of defence against respiratory viruses, which remain among the leading causes of mortality from communicable diseases worldwide. Pattern recognition receptors, including Toll-like receptors, RIG-I-like receptors, NOD-like receptors and DNA sensors such as cGAS-STING, detect viral components and trigger the production of type I interferons and pro-inflammatory cytokines. The review stresses that this signalling must remain in homeostatic balance: excessive activation produces hyperinflammation and tissue damage, while insufficient activation permits viral spread.
Non-coding RNAs add a regulatory layer over nearly every node of these pathways. MicroRNAs typically bind to the 3′ untranslated region of target messenger RNAs, causing degradation when the seed sequence matches completely or translational repression when the match is partial. Long non-coding RNAs, which are more abundant and more varied than microRNAs, act through protein interactions and by sponging other RNAs. Circular RNAs, whose covalently closed structure makes them unusually stable, regulate immune signalling through microRNA sponging and RNA-binding protein interactions. For example, hsa_circ_0000479 sponges miR-149-5p, which would otherwise target the messenger RNA of the viral sensor RIG-I, thereby stabilising antiviral signalling, while circVAMP3 binds the influenza proteins NS1 and NP and prevents them from suppressing RIG-I signalling.
The review also documents how these molecules act at the earliest stage of infection, viral entry. miR-199a inhibits expression of ST6GAL1, the enzyme that synthesises the sialic acid-modified receptors influenza uses to enter cells, and miR-155 may reduce expression of non-canonical entry receptors such as DC-SIGN and MHC-II. For SARS-CoV-2, elevated miR-200c in the plasma of COVID-19 patients is associated with reduced ACE2 expression, limiting viral attachment, and lnc-GAS5, whose serum levels fall with disease severity, appears to regulate the miR-200/ACE2 axis. Several microRNAs, including let-7c-5p, miR-98, miR-199a and miR-214, are reported to modulate TMPRSS2, another host enzyme required for viral entry, although the authors note that experimental evidence for these interactions remains limited.
During replication, non-coding RNAs can bind viral genomes directly. miR-188-3p interacts with the PB2 component across multiple influenza A strains, suggesting broad-spectrum antiviral activity, while miR-324 binds the viral RNA encoding the PB1 subunit of the RNA-dependent RNA polymerase and also enhances interferon and interferon-stimulated gene expression by targeting CUEDC2, a negative regulator of JAK1-STAT3 signalling. miR-150-5p targets the nsp10 RNA of SARS-CoV-2, attenuating both replication and nsp10-mediated immune evasion, and its reduced levels in patient plasma suggest it is depleted as infection progresses.
Viruses, in turn, evolve escape mechanisms. A mutant form of the NS1 protein of the pandemic H1N1 strain found in clinical isolates evades targeting by miR-1307-3p, and the SARS-CoV-2 strain Wuhan-Hu-1 has been reported to evade binding of miR-3232 and miR-4650 to the nsp3 gene. The authors describe this as a dynamic host-virus arms race that underscores the evolutionary significance of RNA-mediated antiviral defence. Viral non-coding RNAs also contribute to immune evasion: subgenomic flaviviral RNAs of dengue virus bind and suppress TRIM25, inhibiting interferon induction.
The regulatory reach of non-coding RNAs extends to interferon pathways and inflammatory cytokines. LncRNA-IVRPIE, which increases in blood immune cells of influenza patients, enhances expression of interferon-beta and multiple interferon-stimulated genes by interacting with hnRNP U to alter chromatin at their transcription start sites. In SARS-CoV-2 infection, the long non-coding RNAs NEAT1 and MALAT1 are upregulated and correlate with elevated IL-6, CCL2 and TNF-alpha, while miR-146a modulates pro-inflammatory cytokines by targeting TRAF6 and IRAK1 in both influenza and coronavirus infections, marking it as a candidate for broad-spectrum antiviral drug development. The review links these mechanisms to the cytokine storm seen in severe disease, in which uncontrolled viral replication drives excessive cytokine production, tissue damage and acute respiratory distress syndrome.
These properties also make non-coding RNAs attractive diagnostic and therapeutic candidates. Circulating microRNA signatures in plasma and respiratory samples reflect infection status and severity, with miR-2392 and miR-29a distinguishing mild from severe COVID-19. Long non-coding RNAs offer tissue- and disease-specific expression, though their low abundance hampers reproducible detection, and circular RNAs combine stability with disease relevance, as shown by circ_0000479 in peripheral blood cells of symptomatic COVID-19 patients. Therapeutically, microRNA mimics and antagomiRs are under clinical investigation, and delivery platforms including lipid nanoparticles, adeno-associated viral vectors, exosomes and inhalable nanoparticles for localised airway delivery are being developed. Circular RNA vaccines for SARS-CoV-2 have shown enhanced stability and prolonged antigen expression compared with linear mRNA platforms, and a circular RNA vaccine elicited higher neutralising antibodies than a modified mRNA vaccine in mice and monkeys against variants of concern.
The authors are careful to delineate the limitations. Many ncRNA effects are context-dependent: the same molecule can be antiviral in one condition and proviral in another, complicating therapeutic predictability. Off-target effects, pleiotropy, inconsistent sample types and detection platforms, immunogenicity of delivery carriers and the absence of large-scale clinical validation all remain barriers. Evidence for ncRNA regulation of metabolic reprogramming and of DNA sensors during respiratory viral infections is still sparse. Antisense approaches have shown promise in mouse models, with antagomirs against miR-93 and miR-146a improving survival during viral infection, but the review concludes that standardised detection, validation in diverse cohorts and rigorous clinical evaluation are needed before non-coding RNAs can transform the management of influenza, SARS-CoV-2 and other emerging respiratory viruses.
Subject of Research: The role of non-coding RNAs in regulating innate immunity during respiratory viral infections
Article Title: Role of non-coding RNA in innate immunity during respiratory viral infections
Article References: Junghare, K. R., Singh, S., Parthasarathy, M., & Kumar, H. (2026). Role of non-coding RNA in innate immunity during respiratory viral infections. Discover Immunity, 3(1), Article 4. https://doi.org/10.1007/s44368-026-00020-3
Image Credits: AI Generated
DOI: 10.1007/s44368-026-00020-3
Keywords: non-coding RNA, innate immunity, influenza, SARS-CoV-2, microRNA, long non-coding RNA, circular RNA, interferon, cytokine storm, biomarkers, RNA therapeutics, pattern recognition receptors
News Source: Kristina Jarvis. (October 30, 2026). Non-coding RNAs Fine-Tune Innate Immunity Against Influenza and Coronaviruses. Scienmag.
