Abstract
Infection of H5N1 influenza virus causes the highest mortality among all influenza viruses. The mechanisms underlying such high viral pathogenicity are incompletely understood. Here, we report that the H5N1 influenza virus encodes a microRNA-like small RNA, miR-HA-3p, which is processed from a stem loop-containing viral RNA precursor by Argonaute 2, and plays a role in enhancing cytokine production during H5N1 infection. Mechanistic study shows that miR-HA-3p targets poly(rC)-binding protein 2 (PCBP2) and suppresses its expression. Consistent with PCBP2 being an important negative regulator of RIG-I/MAVS-mediated antiviral innate immunity, suppression of PCBP2 expression by miR-HA-3p promotes cytokine production in human macrophages and mice infected with H5N1 virus. We conclude that miR-HA-3p is the first identified influenza virus-encoded microRNA-like functional RNA fragment and a novel virulence factor contributing to H5N1-induced 'cytokine storm' and mortality.
Highlights
The sporadic transmission of the highly pathogenic H5N1 avian influenza virus from poultry to human beings in many countries highlights the threat to public health
All of these prompted us to hypothesize that the H5N1 influenza virus, as an RNA virus, may encode miRNA-like small RNA fragments, which in turn, can contribute to the deadly H5N1 infections in a similar way as certain exogenous miRNAs reported in modulating the host cell functions [23, 24]
To determine whether H5N1 influenza virus is capable of encoding miRNA-like small RNA, small RNA (< 30 nt) extracted from A549 cells infected with H5N1 influenza virus (A/Jiangsu/1/2007(H5N1), MOI = 1) for 48 h was sequenced by Solexa deep-sequencing technology
Summary
The sporadic transmission of the highly pathogenic H5N1 avian influenza virus from poultry to human beings in many countries highlights the threat to public health. In the present study, employing Solexa sequencing, northern blot and quantitative RT-PCR assays, we confirmed that H5N1 influenza virus encodes a miRNA-like small RNA, miR-HA-3p.
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