Toxoplasma gondii hijacks host S100A6 to enhance cell migration and brain cyst formation.

Toxoplasma gondii (T. gondii) has the ability to disseminate widely in the host, including crossing the blood brain barrier (BBB) to establish persistent brain cysts. However, the molecular mechanism by which T. gondii hijacks host immune cell migration to facilitate its own dissemination remain incompletely understood. Here we show that T. gondii infection upregulates S100A6 via a calcium and P65-dependent pathway; This elevated S100A6 expression promoted its interaction with filamin A, leading to promoted cytoskeletal reorganization, enhanced cell migration and T. gondii replication. Furthermore, S100A6 knockout in C57BL/6 J mice decreases BBB permeability, inhibits tachyzoite traversal into the brain, and results in fewer and smaller brain cysts. These findings identify S100A6 as a critical regulator of T. gondii induced cell migration and dissemination, and suggest that targeting S100A6 or its downstream signaling can offer therapeutic strategies to limit parasite spread and prevent chronic neuro-toxoplasmosis.