Two groups of people living in dengue endemic area were classified as susceptible (SD) or resistant (RD) to dengue virus (DENV) infection according to their anti-DENV antibody status. The miRNome from monocytes of 7 individuals of each group was assessed upon mock- or DENV-2 infection
Dengue virus (DENV) is a global health threat, with approximately 390 million dengue infections annually, causing dengue fever with mild clinical symptom to life-threatening dengue hemorrhagic fever and dengue shock syndrome. MicroRNA have emerged as important post-transcriptional regulators of gene expression which may play a crucial role in host resistance to DENV. We enrolled 2 groups of Thai population, hypothesized as low susceptible or high susceptible to DENV infection according to their anti-DENV antibody status -one group exhibiting antibodies against 4 serotypes of DENV, and the other group lacking those antibodies-. Monocytes of 7 individuals of each group have been mock or DENV-2 infected and their miRNA transcriptional profile analyzed, 6h post infection. Dysregulated miRNAs were chosen as candidates for functional studies. Mimics of those candidates were transfected into HeLa cell lines and DENV entry and production was measured. Transcriptomic profile of transfected cells was assessed by RNA-Seq to look for miRNA targets. Differential expression analysis of miRNA showed significantly overexpressed miRNA in low susceptible group upon infection, among which miR-155-5p, that we functionally validated. Transfection of miR-155 mimics in HeLa cells induce a decreased percentage of infected cells and a decreased viral titer, 48h after DENV-1, -2 and -4 infection. The transcriptome analysis from miR-155-5p mimic transfected cells revealed some genes involved in anti-viral interferon response: HMOX1 is overexpressed through the downregulation of its transcriptional repressor, BACH1 a miR-155-5p target gene, leading to inhibition of DENV NS2B/NS3 protease activity. Our approach is prone to detect new signaling pathways, highlighting the regulatory role and mechanisms of miRNA in the resistance to DENV infection.