Mia C Somenzi, Kameron T Bell, Abigail M Bitters, Collin S Stratton, Samantha R Springston, Kamryn E Zadeii, Rylee J Anderson, Avery V Stanley, Daisy Woellner-Santos, Scott G Canfield, Américo H López-Yglesias
The obligate intracellular parasite Toxoplasma gondii infects nearly one-third of the global population, yet its impact on human blood-brain barrier (BBB) function remains poorly defined. In this study, we use human induced pluripotent stem cell-derived (iPSC) brain-like microvascular endothelial cells (BMECs), a physiologically relevant BBB model, to investigate if T. gondii infection directly compromises barrier integrity. We show that infection induces robust monocyte chemotactic protein-1 (also known as CCL2) secretion from BMECs, and that CCL2 itself serves as a previously unrecognized driver of BBB dysfunction. Notably, interferon-gamma (IFN-γ) limits BMEC-derived CCL2 release and protects against parasite-mediated barrier damage. These findings identify an IFN-γ-dependent, BMEC-intrinsic defense mechanism that helps preserve central nervous system (CNS) integrity during infection. Collectively, this work establishes a mechanistic foundation for understanding how T. gondii disrupts the human BBB and reveals a novel protective role for IFN-γ in mitigating CNS barrier dysfunction.