Immunomimetic Designer Cells Protect Mice from MRSA Infection

Abstract

Summary 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

MicroRNA-127 Promotes Anti-microbial Host Defense through Restricting A20-Mediated De-ubiquitination of STAT3

“…We thus discover an unappreciated regulatory paradigm linking non-coding miRNA and STAT3 ubiquitination and phosphorylation that has a key role in coordinating anti-microbial immunity. The findings extend our understanding about host-pathogen interaction and provide potential targets for combating highly drug-resistant bacteria such as MRSA (Baral et al, 2018;Liu et al, 2018).…”

Engineering Biomaterials to Direct Innate Immunity

“…The surface of medical implants are likely sites for bacterial biofilm formation, and the inability to treat biofilms on implant surfaces often necessitates implant removal. [43] This work demonstrated that genetically engineering innate immune mechanisms to control cell function can combat an emerging drug-resistant bacterial health threat. One team recently tackled this challenge by engineering cells to secrete an antimicrobial enzyme, lysostaphin ( Figure 2D).…”

Synthetic biology: engineering order in organisms across scales and species

“…In mice models, they are able to diagnose, prevent and treat MRSA infections. Used with permission from [6]. …”

“…Martin Fussenegger at ETH Zrich and Nina Khanna at the University of Basel (both Switzerland), along with their colleagues, used synthetic biology to engineer cells that short-cut the flow of information in the mammalian immune system to thwart methicillin-resistant Staphylococcus aureus (MRSA) infections [6]. …”