LAUSR

Abstract Infection with the mosquito transmitted dengue virus (DENV) remains a significant worldwide public health problem. While the majority of infections are asymptomatic, infection can result in a range of symptoms. MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression through repression or degradation of mRNAs. To understand the contribution of miRNAs to DENV 2 replication, we screened a number of candidate miRNAs for variations in expression levels during DENV 2 infection of HepG2 (liver) cells. Seven miRNAs were identified as differentially expressed, and one, miR‐21, was differentially expressed at all time points examined. Interestingly, miR‐21 was also differentially regulated in DENV 2 infection under conditions of antibody dependent enhancement of infection, and in direct Zika virus infection, but not in DENV 4 infection. The role of miR‐21 during DENV infection was further examined by treating HepG2 cells with an anti‐miR‐21 (AMO‐21) before DENV infection. The results showed a significant reduction in DENV 2 production, clearly suggesting that miR‐21 plays a key role in DENV 2 replication. To further confirm the role of miR‐21 in DENV infection, a peptide nucleic acid‐21 (PNA‐21) construct with a nucleotide sequence complementary to AMO‐21, was co‐administered with AMO‐21 as an AMO‐21/PNA‐21 complex followed by DENV 2 infection. The results showed that AMO‐21 significantly reduced DENV 2 titer, PNA‐21 significantly increased DENV 2 titer and the combined AMO‐21/PNA‐21 showed no difference from non‐treated infection controls. Taken together, the results show that miR‐21 promotes DENV 2 replication, and this mechanism could serve as a possible therapeutic intervention point. HighlightsmiR‐21 played a key role in DENV 2 replication in HepG2 cells.miR‐21 was differentially expressed at all time points examined.miR‐21 promotes DENV 2 replication in HepG2 cells.Anti‐miRNA‐21 oligonucleotide (AMO‐21) significantly reduced DENV 2 titer.