Immunomimetic Designer Cells Protect Mice from MRSA Infection

Highlights•A closed-loop gene network with bacterial sense-and-destroy actuation•Direct diagnosis of implant-associated infections through blood biomarkers•Early prevention of MRSA infection, as well as biofilm formation, in vivo•Curing acute MRSA infections as an alternative to antibiotic therapySummaryMany 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/cms/asset/4d3a7f9c-bbee-4429-b4ab-c174913d84a7/mmc2.mp4Loading ...Download video (mp4, 44 MB)Graphical abstract