Inflammatory responses generated during virus infections are critical for antiviral immune responses. The exact virus recognition elements that activate cells to induce pro-inflammatory signals are not completely characterized. Virus recognition elements such as dsRNA and 5′-triphosphate single-stranded RNA are recognized by several cellular pathways. The intracellular or extracellular interaction of cells with virus recognition elements results in activation of innate immune responses as indicated by expression of inflammatory cytokines and chemokines. In addition to the innate immune inflammation, virus recognition elements trigger establishment of an antiviral state, under which each cell resists virus infection. The resistance to virus infection is in part through inhibition of virus replication by perturbation of RNA and protein synthesis. Determining the exact mechanisms by which immune and antivirus responses are activated is essential for understanding virus pathogenesis.
RNA with high inosine content is not commonly found in normally growing eukaryotic cells but it is present during infections with DNA and RNA viruses such as polyomavirus, Rous-associated virus, vesicular stomatitis virus, measles virus, and respiratory syncytial virus. Extracellular Ino-RNA is generated during virus infections. Cell lysis occurs frequently during virus infections, which results in the release of cell content, including intracellular generated Ino-RNA, into the extracellular space. Extracellular dsRNA has been shown to be able to stimulate antiviral responses in neighboring, uninfected cells.
Using RSV infection as a model, this paper reports that the presence of inosines in ssRNA is a potent inducer of inflammatory cytokines and the antiviral state during virus infection and suggests that Ino-RNA, of virus or cellular origin, in the surrounding tissue after release from infected cells is a signal for the presence of virus infections.
Inosine-Containing RNA Is a Novel Innate Immune Recognition Element and Reduces RSV Infection. (2011) PLoS ONE 6(10): e26463. doi:10.1371/journal.pone.0026463
During viral infections, single- and double-stranded RNA (ssRNA and dsRNA) are recognized by the host and induce innate immune responses. The cellular enzyme ADAR-1 (adenosine deaminase acting on RNA-1) activation in virally infected cells leads to presence of inosine-containing RNA (Ino-RNA). Here we report that ss-Ino-RNA is a novel viral recognition element. We synthesized unmodified ssRNA and ssRNA that had 6% to16% inosine residues. The results showed that in primary human cells, or in mice, 10% ss-Ino-RNA rapidly and potently induced a significant increase in inflammatory cytokines, such as interferon (IFN)-β (35 fold), tumor necrosis factor (TNF)-α (9.7 fold), and interleukin (IL)-6 (11.3 fold) (p