Posted in Dengue, Resource

Increased adaptive immune responses and proper feedback regulation protect against clinical dengue

Genes related to antigen presentation were significantly increased in the asymptomatic compared to the symptomatic dengue individuals. Manuscript by E Simon-Lorière et al., Science Translational Medicine, 2017.

Dengue infections can be asymptomatic, symptomatic, or occasionally progress to severe dengue, a life-threatening condition characterised by a cytokine storm, vascular leakage, and shock. However, the molecular and immunological mechanisms underlying asymptomatic dengue virus (DENV) infection remains largely unknown.

In the publication, E Simon-Lorière et al recruited DENV infected children in Cambodia. Nine individuals remained strictly asymptomatic at the time of inclusion and during the 10-day follow-up period. PBMCs from 8 asymptomatic DENV-1 viremic individuals and 25 symptomatic dengue patients were used for further gene expression analysis.

Asymptomatic individuals have an increase in the percentage of CD4+ T cells and a decrease in CD8+ T cells compared to symptomatic dengue individiuals. However, CD14+ monocytes, Lin-CD11c+ dendritic cells, CD19+ B cells, and CD335+ natural killer cells are not significantly different between asymptomatic and symptomatic individuals.

Transcriptomic signatures were distinct between asymptomatic and symptomatic individuals. The top pathways that diverge the most between asymptomatic and clinical dengue individuals were related to immune processes. Notably, the transcriptomic differences cannot be explained by differences in viral load or immune status.

The innate immune responses were not significantly different between the asymptomatic and symptomatic individuals. Instead, the most significantly activated pathway in asymptomatic individuals was related to “nuclear factor of activated T-cells (NFAT) mediated regulation of immune response.” These genes include CIITA, CD74 and various human leukocyte antigen (HLA) genes, where their expression differences were also validated at the protein levels (See figure on top).

Protein kinase Cq (PKCq) signaling in T lymphocytes was also highly activated in asymptomatic viremic individuals. Genes upregulated included AKT3, SOS1, PAK1, and SLAMF6, as well as T-cell costimulatory pathways such as ICOS-ICOSL, and CD28 and CTLA4 signaling in cytotoxic T-cells.

In contrast, genes related to B-cell activation, differentiation and plasma cell development (BLIMP-1, IRF4) were downregulated in asymptomatic individuals. This finding is correlated with the reduction in antibody production in the asymptomatic individuals.

Data is saved in Gene Expression Omnibus under accession number GSE100299

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