Transcriptional Landscapes of Dengue Patients Reveal Associations with HERV Activity with Severity

Abstract Human endogenous retroviruses (HERVs), remnants of ancient viral infections, are increasingly recognized as potential regulatory elements influencing gene expression and immune responses. However, their role in infectious disease severity remains poorly understood. Here, we investigate the transcriptional impact of HERVs in dengue disease progression by leveraging RNA sequencing data from a large cohort of hospitalized patients across different severity subgroups. We identify differentially expressed HERVs and their co-expressed genes, revealing a severity-dependent transcriptional signature. Notably, genes co-expressed with HERVs in severe dengue were enriched in pathways related to immune modulation, phagocytosis, infectious disease response, and calcium signaling. We further demonstrate that HERVs may regulate genes through co-localization and chromatin interactions, with several HERV-gene pairs residing within same topologically associated domains (TADs). Using promoter interaction analysis, we identify potential regulatory mechanisms, exemplified by the interaction between HERV elements and MAGI3, an immune-modulatory gene. Validation in an independent cohort of 78 patients confirmed reproducibility of HERV expression patterns. Interestingly, genes encoding HERV envelope proteins, known for their immunomodulatory and antiviral properties, were consistently downregulated in severe dengue across both cohorts. These findings suggest a role for HERVs in shaping host transcriptional responses to dengue, with potential implications for disease progression and severity.