Abstract
BackgroundMultiple interplays between viral and host factors are involved in influenza virus replication and pathogenesis. Several small RNAs have recently emerged as important regulators of host response to viral infections. The aim of this study was to characterize the functional role of hsa-miR-1975, a Y5 RNA-derived small RNA, in defending influenza virus and delineate the mechanisms.MethodsWe performed high throughput sequencing of small RNAs in influenza virus-infected cells to identify up- or down- regulated small RNA species. The expression of the most abundant RNA species (hsa-miR-1975) was validated by stem-loop reverse transcription-polymerase chain reaction (RT-PCR). Antiviral effects of hsa-miR-1975 were confirmed by Western Blot, RT-PCR and plaque assay. In vitro perturbation of hsa-miR-1975 combined with exosomes isolation was used to elucidate the role and mechanism of hsa-miR-1975 in the context of antiviral immunity.ResultsSmall RNA sequencing revealed that hsa-miR-1975 was the most up-regulated small RNA in influenza virus-infected cells. The amount of intracellular hsa-miR-1975 increased in the late stage of the influenza virus replication cycle. The increased hsa-miR-1975 was at least partially derived from degradation of Y5RNA as a result of cellular apoptosis. Unexpectedly, hsa-miR-1975 mimics inhibited influenza virus replication while hsa-miR-1975 sponges enhanced the virus replication. Moreover, hsa-miR-1975 was secreted in exosomes and taken up by the neighboring cells to induce interferon expression.ConclusionsOur findings unravel a critical role of Y-class small RNA in host’s defense against influenza virus infection and reveal its antiviral mechanism through exosome delivery. This may provide a new candidate for targeting influenza virus.
Highlights
Influenza virus continually threatens public health and antiviral drug resistance has become a major concern for clinical management [1]
Identification of human small RNA species involved in influenza a virus infection To search for the small RNAs likely participating in influenza A virus (IAV) infection, we performed deep sequencing of small RNAs from influenza virus (A/WSN/33)-infected and uninfected A549 cells, a human lung epithelial cell line (Fig. 1a)
At least 5 RNA species were up-regulated by more than two folds in the infected cells, while 5 other RNA species were downregulated to similar extent (Additional file 1: Figure S1). Among these ten small RNAs, miR-886, miR378 and miR-151 had been previously reported to be associated with influenza virus infection, strengthening the reliability of our method [8, 27, 28]
Summary
Influenza virus continually threatens public health and antiviral drug resistance has become a major concern for clinical management [1]. Identification of host factors involved in viral replication may aid in understanding the interplay between virus and host, as well as in finding new targets for the development of antiviral compounds. Current evidence indicates that host microRNAs (miRNA, typically 21–25 nucleotides long) can. Y RNAs, typically 83–112-nucleotides long, belong to another class of small non-coding RNAs and are involved in a range of cellular processes, including DNA replication, RNA stability and cellular stress responses [10]. Multiple interplays between viral and host factors are involved in influenza virus replication and pathogenesis. Several small RNAs have recently emerged as important regulators of host response to viral infections. The aim of this study was to characterize the functional role of hsa-miR-1975, a Y5 RNA-derived small RNA, in defending influenza virus and delineate the mechanisms
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