Influenza Virus Proteins Block Host Cell Interference with RNA Defense Mechanism

To overcome infection by influenza A virus (IAV), host cells must generate a specific class of short interfering RNA (siRNA), an undertaking actively inhibited by the virus.

SiRNAs have a well-defined structure: a short (usually 21 base pairs) double-stranded RNA (dsRNA) with phosphorylated 5' ends and hydroxylated 3' ends with two overhanging nucleotides. The Dicer enzyme (an endoribonuclease in the RNase III family that cleaves double-stranded RNA and pre-microRNA (miRNA) into short double-stranded RNA fragments) catalyzes production of siRNAs from long dsRNAs and small hairpin RNAs. These small RNAs can bind to other specific messenger RNA (mRNA) molecules and either increase or decrease their activity, for example by preventing an mRNA from producing a protein. RNA interference has an important role in defending cells against parasitic nucleotide sequences – viruses and transposons – but also in directing development as well as gene expression in general.

Previous studies showed that RNAi (RNA interference) is a common antiviral defense in plants, insects and nematodes and that in order to succeed viral infections in these organisms require active suppression of siRNAs by specific viral proteins. Plant and insect viruses have evolved diverse virulence proteins to suppress RNAi as their hosts produce virus-derived small interfering RNAs (siRNAs) that direct specific antiviral defense by an RNAi mechanism dependent on the slicing activity of Argonaute proteins (AGOs).

Argonaute proteins are the catalytic components of the RNA-induced silencing complex (RISC), the protein complex responsible for RNA interference (RNAi) gene silencing. Argonaute proteins bind different classes of small non-coding RNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs), and Piwi-interacting RNAs (piRNAs). Small RNAs guide Argonaute proteins to their specific targets through sequence complementarity, which typically leads to silencing of the target. Some of the Argonaute proteins have endonuclease activity directed against messenger RNA (mRNA) strands that display extensive complementarity to their bound small RNA, and this is known as Slicer activity. These proteins are also partially responsible for selection of the guide strand and destruction of the passenger strand of the siRNA substrate.

In the current study, investigators at Harvard Medical School (Boston, MA, USA) and at the University of California, Riverside (USA) sought to identify the mechanism used by influenza A virus to suppress production of siRNAs in animal cells.

They reported in the December 5, 2016, online edition of the journal Nature Microbiology that mature human somatic cells produced abundant virus-derived siRNAs co-immunoprecipitated with AGOs in response to IAV infection. Creation of viral siRNAs in infected human cells was mediated by the Dicer enzyme and was potently suppressed by both the NS1 protein of influenza A virus and a protein (virion protein 35, or VP35) found in Ebola and Marburg viruses.

Senior author Dr. Kate L. Jeffrey, assistant professor of medicine at Harvard Medical School, said, "Our studies show that the antiviral function of RNAi is conserved in mammals against distinct RNA viruses, suggesting an immediate need to assess the role of antiviral RNAi in human infectious diseases caused by RNA viruses, including Ebola, West Nile, and Zika viruses."

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Harvard Medical School
University of California, Riverside