A comparative analysis of the immunotranscriptomic features of DENV-1, -3, and -4 human challenge models
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE333412 | GEO | 2026/07/01
REPOSITORIES: GEO
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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.
2024-10-21 | GSE276766 | GEO
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.
2021-01-01 | GSE154386 | GEO
Project description:The ability of many viruses to manipulate the host antiviral immune response often results in complex host-pathogen interactions. In order to study the interaction of dengue virus (DENV) with the Aedes aegypti immune response, we have characterized the DENV infection-responsive transcriptome of the immune-competent A. aegypti cell line Aag2. As in mosquitoes, DENV infection transcriptionally activated the cell line Toll pathway and a variety of cellular physiological systems. Most notably, however, DENV infection down-regulated the expression levels of numerous immune signaling molecules and antimicrobial peptides (AMPs). Functional assays showed that transcriptional induction of AMPs from the Toll and IMD pathways in response to bacterial challenge is impaired in DENV-infected cells. In addition, Escherichia coli, a gram-negative bacteria species, grew better when co-cultured with DENV-infected cells than with uninfected cells, suggesting a decreased production of AMPs from the IMD pathway in virus-infected cells. Pre-stimulation of the cell line with gram-positive bacteria prior to DENV infection had no effect on DENV titers, while pre-stimulation with gram-negative bacteria resulted in an increase in DENV titers. These results indicate that DENV is capable of actively suppressing immune responses in the cells it infects, a phenomenon that may have important consequences for virus transmission and insect physiology. Infected (dengue virus or heat-inactivated dengue virus) vs. naive cells. 3 replicates each.
2011-10-31 | E-GEOD-33274 | biostudies-arrayexpress
Project description:tRNA-derived small RNA including tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs) plays significant roles in the various molecular mechanisms that underlie certain human diseases. of the generation of tRFs/tiRNAs and their potential roles during Dengue virus (DENV) infection is not yet known. Here, we have performed small RNA sequencing to identify the generation and alterations in tRF expression profiles of DENV infected Huh7 cells. Our results suggest that 733 tiRNAs/tRFs were found to be differentially expressed during DENV infection. Interestingly, 3’tRF population were found to be upregulated and i-tRF population were found to be downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to analyze the impact of differentially expressed tRFs on DENV pathogenesis. Our results suggest the significant involvement in transcriptional regulation via RNA polymerase II promoter and metabolic pathways. Overall, our study contributes significantly to our understanding of the roles played by tRFs in the complex dynamics of DENV infection.
2024-08-10 | GSE245081 | GEO
Project description:Background. Dengue caused by dengue virus (DENV) serotypes -1 to -4 is the most important mosquito-borne viral disease in the tropical and sub-tropical countries worldwide. Yet many of the pathophysiological mechanisms of host responses during DENV infection remain largely unknown and incompletely understood. Methods. Using a mouse model, the miRNA expressions in liver during DENV-1 infection was investigated using high throughput miRNA sequencing. The differential expression of miRNAs were then validated by qPCR, followed by target genes prediction. The identified miRNA targets were subjected to gene ontology (GO) annotation and pathway enrichment analysis to elucidate the potential biological pathways and molecular mechanisms associated with DENV-1 infection. Results. A total of 224 and 372 miRNAs out of 433 known mouse miRNAs were detected in the livers of DENV-1-infected and uninfected mice, respectively; of these, 207 miRNAs were present in both libraries. The miR-148a-3p and miR-122-5p were the two most abundant miRNAs in both groups. Thirty-one miRNAs were found to have at least 2-fold change in upregulation or downregulation, in which seven miRNAs were upregulated and 24 miRNAs were downregulated in the DENV-1-infected mouse livers. The miR-1a-3p was found to be the most downregulated miRNA in the DENV-1-infected mouse livers, with a significant fold change of 0.10. To validate the miRNA sequencing result, the expression pattern of 12 miRNAs, which were highly differentially expressed or most abundant, were accessed by qPCR and nine of them correlated positively with the one observed in deep sequencing. In silico functional analysis revealed that the adaptive immune responses involving TGF-beta, MAPK, PI3K-Akt, Rap1, Wnt and Ras signalling pathways were modulated collectively by 23 highly differentially expressed miRNAs during DENV-1 infection. Conclusion. This study provides the first insight into the global miRNA expressions of mouse livers in response to DENV-1 infection in vivo and the possible roles of miRNAs in modulating the adaptive immune responses during DENV-1 infection.
2019-03-05 | GSE123346 | GEO
Project description:The ability of many viruses to manipulate the host antiviral immune response often results in complex host-pathogen interactions. In order to study the interaction of dengue virus (DENV) with the Aedes aegypti immune response, we have characterized the DENV infection-responsive transcriptome of the immune-competent A. aegypti cell line Aag2. As in mosquitoes, DENV infection transcriptionally activated the cell line Toll pathway and a variety of cellular physiological systems. Most notably, however, DENV infection down-regulated the expression levels of numerous immune signaling molecules and antimicrobial peptides (AMPs). Functional assays showed that transcriptional induction of AMPs from the Toll and IMD pathways in response to bacterial challenge is impaired in DENV-infected cells. In addition, Escherichia coli, a gram-negative bacteria species, grew better when co-cultured with DENV-infected cells than with uninfected cells, suggesting a decreased production of AMPs from the IMD pathway in virus-infected cells. Pre-stimulation of the cell line with gram-positive bacteria prior to DENV infection had no effect on DENV titers, while pre-stimulation with gram-negative bacteria resulted in an increase in DENV titers. These results indicate that DENV is capable of actively suppressing immune responses in the cells it infects, a phenomenon that may have important consequences for virus transmission and insect physiology.
2011-10-31 | GSE33274 | GEO
Project description:MicroRNAs have emerged as relevant players in resistance to infection. We aimed to identify miRNAs involved in natural resistance to dengue infection. Two groups of people living in dengue endemic area were classified as susceptible (SD) or resistant (RD) to dengue virus (DENV) infection according to their anti-DENV antibody status. We hypothesized that anti-DENV seronegative individuals may represent a population resistant to DENV infection. The miRNome from monocytes of 7 individuals of each group was assessed upon mock- or DENV-2 infection.Dysregulated miRNAs were chosen as candidates for functional studies.
2025-02-12 | E-MTAB-13628 | biostudies-arrayexpress
Project description:Zika virus (ZIKV), a pathogen of global health concern, is transmitted to humans by Aedes mosquitoes. However, the molecular interactions between the vector and the virus remain largely unexplored. We demonstrated that ZIKV and dengue virus (DENV) have similar tropism and infection kinetics in two mosquito strains with different degrees of susceptibility to infection. Comparison of Aedes aegypti’s molecular responses to ZIKV and DENV infection indicated that around 40% of the mosquito’s infection-responsive transcriptome is virus-specific. Regulated genes also included key factors of the mosquito’s anti-viral immunity, pointing to the possible involvement of the Toll innate immune pathway. Comparison of ZIKV and DENV infection-responsive transcriptome data to those for yellow fever virus and West Nile virus identified 26 genes likely to play key roles in virus infection of Aedes mosquitoes. Through reverse genetic analyses, we showed that the Toll and the Jak/Stat innate immune pathways mediate increased resistance to ZIKV infection, and the virus use vATPase and inosine-5’-monophosphate dehydrogenase as mosquito’s host factors.
2017-11-07 | GSE96605 | GEO
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Project description:Host factors are essential for efficient amplification of Dengue virus (DENV), yet the current knowledge of these cellular proteins remains limited. Here, we used quantitative thiouridine cross-linking mass spectrometry (qTUX-MS) to cross-link proteins to viral RNA during a live DENV infection in cell culture. We identified 79 novel host proteins that have not been previously implicated in DENV infection, and demonstrated the reliability of qTUX-MS by validating a subset of these factors. Analysis of proteome changes revealed critical pathways up- and down-regulated during DENV infection, while the levels of qTUX-MS identified factors remained largely unchanged. Knockdown of HMCES, RBMX and hnRNP F reduced the levels of both intracellular viral RNA and DENV titers, suggesting roles in viral amplification prior to packaging and release. In contrast, knockdown of hnRNP M or NONO caused a dramatic drop in viral titers without impacting viral RNA accumulation, indicating a role downstream of DENV replication. Importantly, none of these five host factors were essential for cell viability or amplification of an unrelated virus, adenovirus, demonstrating that knockdown of these host factors did not reduce cell fitness for viral amplification. Thus, qTUX-MS can be used to identify host factor interactions for any RNA virus.
2016-09-26 | PXD003593 | Pride