Folic acid protects against Toxoplasma gondii antigen-induced vascular injury via the CD36-autophagy-lysosomal axis.

Whether and how pathogen-derived antigens themselves drive vascular injury remains an unresolved question in infection biology and cardiovascular research. Using murine model and human pluripotent stem cell-derived vascular organoids (VOs), we demonstrate that Toxoplasma gondii (T. gondii) infection or exposure to its soluble tachyzoite antigens (STAg) compromises vascular integrity, leads to the impairment of endothelium, and heightens inflammation. Mechanistically, STAg upregulates the scavenger receptor CD36 on endothelial cells (ECs), reprogramming them toward a scavenger endothelial cell (SEC)-like phenotype. This shift enhances CD36‑dependent antigen uptake and subsequently perturbs the macroautophagy/autophagy-lysosomal pathway (ALP), culminating in cellular homeostasis disruption. Interestingly, prophylactic folic acid (FA) ameliorates T. gondii STAg-induced vascular injury. FA acts by suppressing CD36 expression, thereby limiting STAg uptake and attenuating ALP hyperactivation, together preserving vascular integrity at the molecular, structural, and metabolic levels. To our knowledge, this study provides the first evidence that pathogen-derived proteins can reprogram ECs into an SEC-like phenotype in a CD36‑dependent manner, with subsequent dysfunction of ALP. Our findings not only identify pathogen-derived proteins as novel mediators of vascular injury but also establish the CD36-ALP axis as a promising therapeutic target. Furthermore, we propose FA as a potent vascular-protective agent.Abbreviation: ALP: autophagy-lysosomal pathway; Chlo: chloroquine; ECs: endothelial cells; ECM: extracellular matrix; ER: endoplasmic reticulum; FA: folic acid; RAPA: rapamycin; SMCs: smooth muscle cells; STAg: soluble tachyzoite antigens; T. gondii: Toxoplasma gondii; TLRs: toll-like receptors; VOs: vascular organoids.