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Cell. 2018 Jul 12;174(2):259-270.e11. doi: 10.1016/j.cell.2018.05.039. Epub 2018 Jun 21.

Immunomimetic Designer Cells Protect Mice from MRSA Infection.

Author information

1
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
2
Laboratory of Infection Biology, Department of Biomedicine, University and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
3
IUT Lyon 1, Département Génie Biologique, 74 Boulevard Niels Bohr, 69622 Villeurbanne Cedex, France.
4
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, 200241 Shanghai, People's Republic of China.
5
Laboratory of Infection Biology, Department of Biomedicine, University and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland. Electronic address: nina.khanna@usb.ch.
6
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland; Faculty of Science, University of Basel, 4031 Basel, Switzerland. Electronic address: fussenegger@bsse.ethz.ch.

Abstract

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.

KEYWORDS:

Toll-like receptor; antibiotic resistance; biofilm; cell therapy; encapsulation; implant-associated infection; lysostaphin; methicillin-resistant Staphylococcus aureus; murine tissue cage infection model; synthetic gene circuit

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