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Antibody-dependent DENV infection induces distinct transcriptomic responses in infected and bystander human macrophages

ABSTRACT: Antibody-dependent DENV infection induces distinct transcriptomic responses in infected and bystander human macrophages

PROVIDER: PRJNA1134216 | ENA |

REPOSITORIES: ENA

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Antibody-dependent DENV infection induces distinct transcriptomic responses in infected and bystander human macrophages

Project description:Antibody-dependent enhancement has been thought to induce differential cellular responses to infection compared to conventional receptor mediated DENV entry. However, the precise mechanisms underlying these responses remain poorly understood. In this work we applied single cell RNA sequencing (scRNA seq) to characterize the transcriptomic profiles of human macrophages infected in enhancing, and non-enhancing infection conditions.

2025-01-13 | GSE271966 | GEO

scRNAseq analysis of DENV-2 infected B cells

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 FcR 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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Detection of DENV infected cells following natural dengue infection

Project description:Viable T cells (CD3+ CD19-) and B cells (CD3- CD19+) were sorted from PBMC samples obtained from 1 individual experiencing a natural secondary DENV infection. Single cell RNA sequencing analysis was performed on 3 time points

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DENV genome project

Project description:Amplicon-based DENV genome

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RNA sequencing of Aedes mosquitoes infected with Zika virus (ZIKV) or Dengue virus (DENV)

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.

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scRNAseq analysis of DENV-2 infected B cells

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Transcriptional analysis of DENV-elicited inflammation following experimental human DENV-1 challenge

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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DENV genome sequencing project

Project description:DENV genome sequencing project

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Project description:The objective of this analysis was to determine the transcriptional signature associated with experimental primary DENV-3 infection in human volunteers. Nine flavivirus naive volunteers were challenged with an attenuated DENV-3 strain - CH53489 - and blood collected for RNA extraction and transcriptional analysis on or around study days 0, 6, 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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