The Mammalian Response to Virus Infection Is Independent of Small RNA Silencing

Abstract

Summary A successful cellular response to virus infection is essential for evolutionary survival. In plants, arthropods, and nematodes, cellular antiviral defenses rely on RNA interference (RNAi). Interestingly, the mammalian response to virus is predominantly orchestrated through interferon (IFN)-mediated induction of antiviral proteins. Despite the potency of the IFN system, it remains unclear whether mammals also have the capacity to employ antiviral RNAi. Here we investigate this by disabling either IFN, small RNA function or both activities in the context of virus infection. We find that loss of small RNAs in the context of an in vivo RNA virus infection lowers titers due to reduced transcriptional repression of the host antiviral response. In contrast, enabling a virus with the capacity to inhibit the IFN system results in increased titers. Taken together, we conclude that small RNA silencing is not a physiological contributor to the IFN-mediated cellular response to virus infection.

Production of functional small interfering RNAs by an amino-terminal deletion mutant of human Dicer

“…However, whether RNAi as originally defined-that is a posttranscriptional regulatory mechanism triggered by long double-stranded RNAs (dsRNAs) (3)-continues to function as an antiviral mechanism in mammalian cells has remained controversial. Most importantly, sequence analysis of small RNAs expressed in mammalian somatic cells infected by a wide range of viruses has failed to detect significant levels of virally derived siRNAs (4-7), whereas human and mouse cells lacking a functional Dicer protein, and hence incapable of producing either siRNAs or miRNAs, are generally very similar to WT cells in terms of their ability to support the replication of a wide range of RNA and DNA viruses (5,6), thus arguing against the existence of a protective RNAi response.…”

Virus Meets Host MicroRNA: the Destroyer, the Booster, the Hijacker

“…However, it is still debatable whether host miRNAs play antiviral roles in the physiological context of infection (43). For example, by global depletion or downregulation of host miRNAs, two recent studies show that the miRNA pathway does not counteract infection by a wide range of viruses in mammalian cells (82,83).…”

Mammalian RNA virus-derived small RNA: biogenesis and functional activity

“…Backes et al used an alternative strategy to determine whether virus-derived small RNA is relevant to the antiviral response in mammalian hosts [41]. They engineered a vesicular stomatitis virus (VSV) carrying VP55, a vaccine virus protein that could inhibit mammalian RNAi by degrading small RNAs [41]. Their results demonstrated that carrying the VP55 protein does not benefit viral replication but enhances virus-induced IFN responses in mammalian hosts.…”

“…These results also implied that mammalian cells mainly use IFNstimulated activity rather than RNAi-derived antivirus responses for preventing viral infection. Backes et al used an alternative strategy to determine whether virus-derived small RNA is relevant to the antiviral response in mammalian hosts [41]. They engineered a vesicular stomatitis virus (VSV) carrying VP55, a vaccine virus protein that could inhibit mammalian RNAi by degrading small RNAs [41].…”