Many community- and hospital-acquired bacterial infections are caused by antibiotic-resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) predisposes humans to invasive infections that are difficult to eradicate. We designed a closed-loop gene network programming mammalian cells to autonomously detect and eliminate bacterial infections. The genetic circuit contains human Toll-like receptors as the bacterial sensor and a synthetic promoter driving reversible and adjustable expression of lysostaphin, a bacteriolytic enzyme highly lethal to S. aureus. Immunomimetic designer cells harboring this genetic circuit exhibited fast and robust sense-and-destroy kinetics against live staphylococci. When tested in a foreign-body infection model in mice, microencapsulated cell implants prevented planktonic MRSA infection and reduced MRSA biofilm formation by 91%. Notably, this system achieved a 100% cure rate of acute MRSA infections, whereas conventional vancomycin treatment failed. These results suggest that immunomimetic designer cells could offer a therapeutic approach for early detection, prevention, and cure of pathogenic infections in the post-antibiotic era. Video Abstract: [Figure presented] Encapsulated mammalian cells with a synthetic gene circuit to sense and respond to MRSA infection could provide potential prophylactic, diagnostic, or therapeutic options for medical implant-associated infections.
CITATION STYLE
Liu, Y., Bai, P., Woischnig, A. K., Charpin-El Hamri, G., Ye, H., Folcher, M., … Fussenegger, M. (2018). Immunomimetic Designer Cells Protect Mice from MRSA Infection. Cell, 174(2), 259-270.e11. https://doi.org/10.1016/j.cell.2018.05.039
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