Epigenetic Locking of Vascular and Inflammatory Effectors Defines the Universal Host Response to Severe Infection

Background : Severe infections—whether bacterial (Tuberculosis), viral (Dengue), or polymicrobial (Sepsis)—converge on a shared phenotype of systemic inflammation and vascular dysfunction. While transcriptional signatures are well characterized, the epigenetic mechanisms predisposing immune cells to this pathological response remain undefined. Methods : We developed the Chromatin Priming Index (CPI), a single-cell metric quantifying the fraction of immune response genes with accessible chromatin ('primed' for activation). We applied CPI to integrated scRNA-seq and scATAC-seq data from active TB (n=10,357 cells), Sepsis (GSE151263; n=24,796 cells), and Dengue (GSE154386; n=20,000 cells). Results : Mean CPI exceeded 80% across all diseases (TB PBMC: 84.2%, Sepsis: 82.5%, Dengue: 76.1%; p=0.16 Kruskal-Wallis), indicating a conserved 'Epigenetic Alert State'. We identified 616 universally primed genes, enriched for interferon response (ISG15, STAT1), inflammation (S100A8/A9), and notably VEGFA—the driver of vascular permeability. VEGFA was upregulated in monocytes with Log2FC correlating with vascular severity: TB +1.21, Sepsis +2.31, Dengue +4.02. Conclusions : Immune cells are epigenetically 'pre-loaded' to produce VEGFA, providing a mechanism for the vascular leak syndrome in severe infection. This identifies chromatin remodeling as a therapeutic target for host-directed intervention.