Abstract
Honeysuckle (Lonicera japonica Thunb) is a traditional Chinese medicine (TCM) with an antipathogenic activity. MicroRNAs (miRNAs) are small non-coding RNA molecules that are ubiquitously expressed in cells. Endogenous miRNA may function as an innate response to block pathogen invasion. The miRNA expression profiles of both mice and humans after the ingestion of honeysuckle were obtained. Fifteen overexpressed miRNAs overlapped and were predicted to be capable of targeting three viruses: dengue virus (DENV), enterovirus 71 (EV71) and SARS-CoV-2. Among them, let-7a was examined to be capable of targeting the EV71 RNA genome by reporter assay and Western blotting. Moreover, honeysuckle-induced let-7a suppression of EV71 RNA and protein expression as well as viral replication were investigated both in vitro and in vivo. We demonstrated that let-7a targeted EV71 at the predicted sequences using luciferase reporter plasmids as well as two infectious replicons (pMP4-y-5 and pTOPO-4643). The suppression of EV71 replication and viral load was demonstrated in two cell lines by luciferase activity, RT-PCR, real-time PCR, Western blotting and plaque assay. Furthermore, EV71-infected suckling mice fed honeysuckle extract or inoculated with let-7a showed decreased clinical scores and a prolonged survival time accompanied with decreased viral RNA, protein expression and virus titer. The ingestion of honeysuckle attenuates EV71 replication and related pathogenesis partially through the upregulation of let-7a expression both in vitro and in vivo. Our previous report and the current findings imply that both honeysuckle and upregulated let-7a can execute a suppressive function against the replication of DENV and EV71. Taken together, this evidence indicates that honeysuckle can induce the expression of let-7a and that this miRNA as well as 11 other miRNAs have great potential to prevent and suppress EV71 replication.
Highlights
Honeysuckle (Lonicera japonica Thunb) is a traditional Chinese medicine (TCM)
15 overlapping miRNAs in the mice and human groups were predicted to be able to target the genome sequences of SARSCoV-2, DENV2 and enterovirus 71 (EV71) (Supplementary Table S1)
These data imply that the ingestion of honeysuckle both in mice and humans could induce a similar group of host miRNAs that have the potential to target the genome of invading pathogens especially RNA viruses such as SARS-CoV-2, dengue virus (DENV)-2 and EV71
Summary
Honeysuckle (Lonicera japonica Thunb) is a traditional Chinese medicine (TCM). The aqueous extract of the flower bud can relieve fever and flu-like symptoms [1]. Among the potential targets for the suppression of SARS-CoV-2, a few studies have investigated repurposing drugs or small molecules that inhibit ACE2 and TMPRSS2 [34,36] These two receptors are detected in many organs and blocking ACE2 or TMPRSS2 may cause unwanted side effects when potential antiviral agents are systemically administrated in patients with multiple comorbidities [37,38]. Our previous study on the antiviral activity of honeysuckle revealed that inducing host innate miRNAs may have the potential to block the spread and infection of various viruses [2] To extend this concept, we attempted to determine whether honeysuckle upregulated let-7a could target EV71 at predicted regions and alleviate its replication and pathogenesis.
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