RNA interference (RNAi) is an evolutionarily conserved post-transcriptional gene silencing mechanism in eukaryotes, and has been well recognized as an antiviral immunity in fungi, plants, and invertebrates.

In the process of antiviral RNAi, viral dsRNA replicative intermediates generated during RNA virus replication are recognized and processed by Dicer into siRNAs. These virus-derived siRNAs (vsiRNAs) are then transferred into RNA-induced silencing complex (RISC), to direct the cleavage of cognate viral RNAs. However, whether RNAi can function as an antiviral defense in mammals, particularly in differentiated mammalian somatic cells, remains unclear for decades. 

In collaboration with Dr. QIN Chengfeng from Beijing Institute of Microbiology and Epidemiology, the researchers from Dr. ZHOU Xi’s group at the State Key Laboratory of Virology, Wuhan Institute of Virology of the Chinese Academy of Sciences, have reported that RNAi can be induced and suppressed by human enterovirus 71 (HEV71), and indeed function as an antiviral immunity in mammals. 

HEV71 infection in infants and young children causes hand-foot-and-mouth disease and severe neurological manifestations, and has emerged as one of the major global threats to public health.

In this work, Dr. ZHOU Xi and his colleagues identified the nonstructural protein 3A of HEV71 as the viral suppressor of RNAi (VSR) that inhibits vsiRNA biogenesis.

When the VSR activity of 3A was impaired, the VSR-deficient viruses effectively triggered RNAi response in both mammalian cells and mice, producing abundant vsiRNAs. These vsiRNAs are Dicer-dependently produced from viral dsRNA, loaded into RISC, and fully active to degrade cognate viral RNAs. 

The VSR-deficient mutants of HEV71 are significantly restricted in human somatic cells and mice, while Dicer deficiency successfully restored HEV71 infection independently of type I interferon (IFN-I) response.

Their findings highlight that RNAi can indeed function as an antiviral immunity in mammals. And it uncovers for the first time the detailed mechanism by which a human RNA virus evades antiviral RNAi both in vitro and in vivo. 

The results have been published in Immunity entitled "Human virus-derived small RNAs can confer antiviral immunity in mammals".  

"This work defines RNAi as a novel antiviral immune pathway in mammals. Given the evolutionary conservation of RNAi in all eukaryotes, RNAi evolves from the simplest eukaryotic organisms to human beings, and keeps combating against viruses," said Dr. QIU Yang, the first author of the paper. 

"Our study is a conceptual advance in antiviral immunity, and should inspire and attract more scientists to this field," said Dr. ZHOU Xi. 

This work was supported by the NSFC Excellent Young Scientist Fund, CAS Strategic Priority Research Program, and Newton Advanced Fellowship of the Royal Society. Researchers from Wuhan University and the Institute of Biochemistry and Cell Biology of CAS also participated in this study. 

Model for the induction and suppression of antiviral RNAi by HEV71 in mammals. (Image by QIU Yang)