Abstract
About 20–25% of dengue virus (DENV) infections become symptomatic ranging from self-limiting fever to shock. Immune gene expression changes during progression to severe dengue have been documented in hospitalized patients; however, baseline or kinetic information is difficult to standardize in natural infection. Here we profile the host immunotranscriptome response in humans before, during, and after infection with a partially attenuated rDEN2Δ30 challenge virus (ClinicalTrials.gov NCT02021968). Inflammatory genes including type I interferon and viral restriction pathways are induced during DENV2 viremia and return to baseline after viral clearance, while others including myeloid, migratory, humoral, and growth factor immune regulation factors pathways are found at non-baseline levels post-viremia. Furthermore, pre-infection baseline gene expression is useful to predict rDEN2Δ30-induced immune responses and the development of rash. Our results suggest a distinct immunological profile for mild rDEN2Δ30 infection and offer new potential biomarkers for characterizing primary DENV infection.
Highlights
About 20–25% of dengue virus (DENV) infections become symptomatic ranging from selflimiting fever to shock
We previously showed that the T-cell response to rDEN2Δ30 is comparable to that observed in natural infection[30]
From our parent cohort of 20 subjects infected with rDEN2Δ30, including both men and women of White or Black race across two different study sites[29], we selected a representative subset of eleven based on viremia onset, duration, and peak titer metrics that matched the variability in these metrics of the parent cohort. This was done to understand how gene expression may change as a function of viral replication characteristics as opposed to studying the role of host background, neither of which has to date been conclusively found to be a determinant of dengue disease
Summary
About 20–25% of dengue virus (DENV) infections become symptomatic ranging from selflimiting fever to shock. Immune gene expression changes during progression to severe dengue have been documented in hospitalized patients; baseline or kinetic information is difficult to standardize in natural infection. Primary infection with a single serotype can cause disease, but the preponderance of disease is associated with secondary heterologous infection[6]. One hypothesis for this involves a reduced ratio of protective neutralizing antibodies versus non-neutralizing cross-reactive antibodies with the latter promoting antibodydependent enhancement of viral replication as discussed elsewhere[7,8]. Most these study designs utilized symptomatic infection cases (often hospitalized patients) and correlated gene expression with clinical status through severe disease to convalescence. A recent meta-analysis of these studies has identified a discrete natural killer (NK) cell-associated 20-gene set signature of severe disease[20]
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