Intravascular exposure to thymocyte selection-associated high mobility group box protein (TOX), a T cell–derived factor elevated after severe infection, impaired endothelial barrier function, upregulated intercellular adhesion molecule-1 (ICAM-1), and, through macrophages, induced fibroblast activation with increased α-smooth muscle actin (α-SMA), fibronectin, and extracellular matrix (ECM) remodeling. Here, ACTA1 is linked to infection.