Immunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model

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.

Single-cell temporal analysis of natural dengue infection reveals skin-homing lymphocyte expansion one day before defervescence

“…In this study, we were able to pinpoint that the type I interferon pathway was most pronounced in monocytes. In earlier studies, the down-regulation of ribosomal and translation genes were seen in early DENV infection ( Hanley et al., 2021 ; Roth et al., 2017 ; Waickman et al., 2021 ). Our detailed analysis showed that the translation-related genes were suppressed the most at Day −2 in monocytes and B cells, which are known to be the direct targets of DENV ( Durbin et al., 2008 ; Upasani et al., 2020 ; Zanini et al., 2018 ), and to a lesser extent in non-DENV-targeted populations such as T cells.…”

“…With the detailed analyses of temporal scRNA-seq profiles, we observed intriguingly consistent trends between the two DENV patients throughout the four time points, both in terms of the dynamics of relative abundances of immune cell types, as well as overall and cell-type specific gene expression patterns. These allowed us to improve the depth of earlier transcriptomic analyses of the host immune response against DENV, which might partly be restricted by the low-resolution bulk RNA-seq and microarray ( Hanley et al., 2021 ; Popper et al., 2012 ; Sun et al., 2013 ; van de Weg et al, 2015 ). Although most of the time-course RNA-seq studies of immune response in dengue patients or in vitro systems were performed using the samples collected during the vaguely defined “acute infection” or “febrile phase” ( Hanley et al., 2021 ; Sun et al., 2013 ; van de Weg et al, 2015 ; Waickman et al., 2021 ), we broke this important period down to three consecutive days, analyzed the single-cell transcriptomic profiles of DENV patients for each day, and compared those with the two-week follow-up baselines.…”

“…For instance, several cytokines have been shown to be associated with DENV infection, specifically at the febrile and critical phases ( Rathakrishnan et al., 2012 ), similar to the levels of the platelet activating factor (PAF), which were seen rising and falling by hours before the critical phase ( Jeewandara et al., 2015 ). High-throughput analyses have also been employed to explore the transcriptional signatures associated with the progression and severities in DENV-infected patients, e.g., ( Banerjee et al., 2017 ; Hanley et al., 2021 ; Popper et al., 2012 ; Simon-Loriere et al., 2017 ). However, these transcriptomic studies on host immune responses against DENV so far largely relied on the “bulk” or population-level analyses, which provide average profiles of the entire immune cells, or those that can be sorted by known surface markers.…”

Knowledge discovery and dengue forecasting applied in a four-year dataset collected at Natal/RN – Brazil

“…For instance, for 2017 the levels of dengue incidence for all neighborhoods of Natal city were considerably lower if compared with the other recorded years. This fact could be related to several aspects such as the presence of susceptible people for the main circulating serotype [21], since Dengue is caused by 4 different virus serotypes [22]. Other aspects such as the complex interaction between environmental drivers and the 4 dengue serotypes could occur [23].…”

Evolution of inflammation and immunity in a dengue virus 1 human infection model

“…Experimental human infection with the DENVs have been documented since 1902 and have greatly contributed to our foundational understanding of DENV transmission, virology, and immunology [15][16][17][18][19][20][21][22][23][24][25]. More recent studies have characterized the clinical and functional immune profiles following DENV-1 or DENV-2 infection, explored the early transcriptional features of attenuated DENV-2 infection, and described the cellular immune responses following infection [9,14,[26][27][28]. However, to date, no study has sought to comprehensively and longitudinally assess and integrate the virologic and immunologic parameters associated with a primary DENV infection in a flavivirus-naïve individual.…”