UC Riverside

Diverse eukaryotic hosts produce virus-derived small interfering RNAs (siRNAs) to direct antiviral immunity by RNA interference (RNAi). However, it has been controversial in the past decade whether the mammalian RNAi pathway has a natural antiviral function. In this dissertation, I demonstrate the production of canonical virus-derived siRNAs processed by endoribonuclease Dicer from viral double-stranded RNA (dsRNA) precursors in cultured hamster and human somatic cells and in mice infected by two distinct RNA viruses after their cognate viral suppressor of RNA silencing (VSR) is rendered inactive. These mammalian viral siRNAs are predominantly 22 nucleotides long and contain mostly uridine as the 5’-terminal nucleotide, and are therefore similar to mammalian microRNAs. I show that canonical viral siRNAs are loaded into mouse and human Argonaute proteins at high levels in the infected cells. Further analysis reveals that the VSR protein NS1 of Influenza A virus inhibits the biogenesis of viral siRNAs whereas the VSR protein B2 of Nodamura virus suppresses both the biogenesis and the Argonaute loading of viral siRNAs during infection. The results together demonstrate that the antiviral RNAi response is conserved in mammals as found in fungi, plants, insects, and nematodes.