Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons

Bracha, Shahar; Johnson, Hannah J; Pranckevicius, Nicole A; Catto, Francesca; Economides, Athena E; Litvinov, Sergey; Hassi, Karoliina; Rigoli, Marco Tullio; Cheroni, Cristina; Bonfanti, Matteo; Valenti, Alessia; Stucchi, Sarah; Attreya, Shruti; Ross, Paul D; Walsh, Daniel; Malachi, Nati; Livne, Hagay; Eshel, Reut; Krupalnik, Vladislav; Levin, Doron

doi:10.5167/uzh-262155

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Bracha, S., Johnson, H. J., Pranckevicius, N. A., Catto, F., Economides, A. E., Litvinov, S., Hassi, K., Rigoli, M. T., Cheroni, C., Bonfanti, M., Valenti, A., Stucchi, S., Attreya, S., Ross, P. D., Walsh, D., Malachi, N., Livne, H., Eshel, R., Krupalnik, V., … Rechavi, O. (2024). Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons. Nature Microbiology, 9, 2051–2072. https://doi.org/10.1038/s41564-024-01750-6

Abstract

Delivering macromolecules across biological barriers such as the blood–brain barrier limits their application in vivo. Previous work has demonstrated that Toxoplasma gondii, a parasite that naturally travels from the human gut to the central nervous system (CNS), can deliver proteins to host cells. Here we engineered T. gondii’s endogenous secretion systems, the rhoptries and dense granules, to deliver multiple large (>100 kDa) therapeutic proteins into neurons via translational fusions to toxofilin and GRA16. We demonstrate delivery