A Comparative Analysis of the Immunotranscriptomic Features of DENV-1, -3, and -4 Human Challenge Models

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BACKGROUND: Dengue virus (DENV) infections cause a range of clinical symptoms, from a mild febrile illness to severe disease. Higher levels of DENV RNAemia are associated with severe dengue, although this relationship is incompletely understood. Dengue Human Infection Models (DHIMs), in which volunteers are experimentally infected with underattenuated DENV strains, provide an invaluable tool for studying early virologic, transcriptional, and immunologic features of infection. DHIM studies using DENV-1, DENV-3, and DENV-4 have demonstrated qualitatively distinct clinical features, however, the contribution of RNAemia and serotype to divergent transcriptional and clinical profiles in these challenge models remains unclear. METHODS: In this work, we performed a comparative analysis of DHIM-1, DHIM-3, and DHIM-4 studies to determine shared and unique features of the transcriptional response to infection and their associations with RNAemia and clinical symptoms. We then exposed primary human PBMC in vitro to DENV-1 or DENV-3 at varying titers and performed bulk RNA sequencing. RESULTS: Across DHIMs, we identified a set of conserved, upregulated genes at day of peak RNAemia, representing a core antiviral response independent of serotype. Further, a unique gene signature indicating downregulated cytoplasmic translation emerged in a subset of DHIM-3 participants with elevated RNAemia and symptomatology. In vitro PBMC exposure to DENV demonstrated that conserved and unique gene expression signatures varied as a function of viral dose rather than serotype. CONCLUSIONS: These data show that viral burden correlates with transcriptional responses and clinical symptomatology following experimental DENV infection, contributing to our understanding of dengue pathogenesis and immunity.

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