Honeysuckle-encoded atypical microRNA2911 directly targets influenza A viruses

Abstract

Influenza A viruses (IAVs), particularly H1N1, H5N1 and H7N9, pose a substantial threat to public health worldwide. Here, we report that MIR2911, a honeysuckle (HS)-encoded atypical microRNA, directly targets IAVs with a broad spectrum. MIR2911 is highly stable in HS decoction, and continuous drinking or gavage feeding of HS decoction leads to a significant elevation of the MIR2911 level in mouse peripheral blood and lung. Bioinformatics prediction and a luciferase reporter assay showed that MIR2911 could target various IAVs, including H1N1, H5N1 and H7N9. Synthetic MIR2911 significantly inhibited H1N1-encoded PB2 and NS1 protein expression, but did not affect mutants in which the MIR2911-binding nucleotide sequences were altered. Synthetic MIR2911, extracted RNA from HS decoction and HS decoction all significantly inhibited H1N1 viral replication and rescued viral infection-induced mouse weight loss, but did not affect infection with a mutant virus in which the MIR2911-binding nucleotide sequences of PB2 and NS1 were altered. Importantly, the inhibitory effect of HS decoction on viral replication was abolished by an anti-MIR2911 antagomir, indicating that the physiological concentration of MIR2911 in HS decoction could directly and sufficiently suppress H1N1 viral replication. MIR2911 also inhibited H5N1 and H7N9 viral replication in vitro and in vivo. Strikingly, administration of MIR2911 or HS decoction dramatically reduced mouse mortality caused by H5N1 infection. Our results demonstrate that MIR2911 is the first active component identified in Traditional Chinese Medicine to directly target various IAVs and may represent a novel type of natural product that effectively suppresses viral infection.

Cross-kingdom inhibition of breast cancer growth by plant miR159

“…Several labs have used PCR to note the absence of individual plant miRNAs that were abundant in a given source before ingestion [27][28][29]; however, our sequencing data as well as others have observed that the plant miRNAs that are taken up after consumption are not necessarily those that are most abundant in the plant (Supplementary information, Table S1) [21,22]. Therefore, there is likely a selective mechanism for the uptake of specific plant miRNAs in mammals.…”

“…However, it has been argued that the inability to detect the uptake of plant miRNAs was due to only looking at a few selected miRNAs rather than using sequencing to screen for all plant miRNAs. Furthermore, the cross-kingdom presence and potential function of plant miRNAs in mammals are supported by independent studies from only two different labs in the past three years, highlighting the need for further verification [22,[34][35][36].…”

“…It is proposed that ingested plant miRNAs are taken up by the gastrointestinal (GI) epithelial cells, which subsequently package the miRNAs into EVs and release them into circulation. A more recent finding by the same group shows that a plant miRNA from honeysuckle is able to inhibit Influenza A replication [22], indicating that plant miRNAs may be useful for treating human diseases. Furthermore, another group recently reported that oral administration of three mammalian miRNAs that have been 2'-O-methylated, like plant miRNAs [23], resulted in the uptake of theses miRNAs in the intestine and the subsequent reduced intestinal tumor burden [24].…”

Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis

“…121,122 A recent study revealed that the long-known beneficial effect of honeysuckle decoction (Lonicera japonica) traditionally used in Chinese medicine against flu might imply miRNA. A rRNA-derivedatypical miRNA, miR-2911 has been identified that is resistant to boiling and can reach an adequate amount in the honeysuckle decoction.…”

Negligible uptake and transfer of diet-derived pollen microRNAs in adult honey bees

“…Nonetheless, controversy remains. [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] The possibility of cross-kingdom regulation of gene expression via ingested miRNAs could be of particular interest in the mutualistic relationships of plants and their pollinators. The relationship involves an exchange of nutrients for the reproduction-enabling service of pollination, but is complicated by the antagonistic relationship of the two players, which is characterized by a fundamental conflict of interest.…”