A host-dependent transcriptional response correlates with Dengue virus infection rate in healthy humans.

Dengue virus (DENV) infection is a major emerging disease in tropical and subtropical countries and the influence of host genetics during early phases of infection remains to be fully elucidated. Here we use dendritic cells (DCs) and macrophages from healthy individuals to establish inter-individual variability in DENV infection and antibody-mediated enhancement (ADE). We show that host-related factors determine the severity of the infection rate both in DENV-infected DCs and macrophages following ADE. We then correlate the inter-individual variability in infection rates with genome-wide transcript abundance measured by RNA sequencing in DCs following DENV infection. We report 190 host-related transcripts in DCs that correlate markedly with infection rates that form an ubiquitin-mediated antiviral network. Furthermore, these transcripts are enriched for glycolysis, which we show is critical for the early phases of infection. Among virus induced transcripts (i.e. significant correlation only after DENV), we identify DUSP10 as the best indicator of the severity of infection. These results indicate the importance of host genetics in shaping the severity of DENV infection rates in DCs and identify novel potential DENV-susceptibility targets. Overall design: Primary human DCs and macrophages were infected with dengue virus or dengue+antibody against dengue for 6 hours. As a control, cells were treated with medium only (DCs) or anti-prM dengue protein only (macrophages). After incubation time, cells were washed with warm PBS before adding 500 µl TRIzol reagent (Invitrogen) and RNA was isolated.