Transcriptional analysis of DENV-elicited inflammation following experimental human DENV-3 challenge
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PROVIDER: PRJNA892993 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptional analysis of DENV-elicited inflammation following experimental human DENV-1 challenge
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Project description:The objective of this analysis was to determine the transcriptional signature associated with experimental DENV-1 infection in human volunteers. Nine flavivirus naive volunteers were challenged with an attenuated DENV-1 strain - 45AZ5 - and blood collected for RNA extraction and transcriptional analysis on days 0, 8, 10, 14, and 28 post challenge using PAXgene collection tubes. Total RNA was isolated from the collection tubes and subjected to RNAseq analysis to identify genes and gene sets that were differentially expressed across the infection time course.
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Project description:Controlled dengue human challenge studies present a unique opportunity to address many longstanding questions in the field of flavivirus biology. These fundamental questions include defining the early immunological signatures of infection, the host/environmental factors that impact disease severity, and the role of preexisting immunity on the development of symptomatic viral infection. However, while several controlled dengue human challenge studies have been performed and appear to clinically recapitulate may features of mild natural DENV infection, limited data are available on how the immunological and transcriptional response elicited by these attenuated challenge viruses compares to the profile associated with a natural, unattenuated DENV infection. To bridge this knowledge gap, we performed scRNAseq analysis on longitudinally collected PBMC samples obtained from 3 individuals (8 time points per subject) enrolled in the SUNY/WRAIR DENV-1 controlled human challenge study. In addition, 3 time points (two acute infection time points, one control time point) from two individuals experiencing a natural DENV-1 infection were analyzed and computationally integrated with the challenge model dataset. This temporally integrated dataset contains a total of 171,208 cells and 22 statistically distinct populations corresponding to all major anticipated leukocyte subsets. While all identified cell populations demonstrated significant and consistant perturbations in their transcriptional profile in response to either natural or experimental DENV infection, conventional monocytes respond most robustly to infection across all subjects and study groups from an unbiased transcriptional perspective. Using these data, core sets of genes that were consistently induced by either natural or experimental DENV were identified, and the overlap between the two arms of the study assessed.
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Project description:Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into FcR expressing cells such as monocytes, macrophages, and dendritic cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. In this study, we demonstrate that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection, with the infection-enhancing activity of the membrane-restricted BCR correlating with the ADE potential of the IgG version of the antibody. In addition, we observed that the frequency of DENV-infectable B cells increases in previously flavivirus-naïve volunteers after a primary DENV infection. These findings suggest that BCR-dependent infection of B cells is a novel mechanism immune-mediated enhancement of DENV-infection.
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