Tunable thermal bioswitches for in vivo control of microbial therapeutics

• Published in: Nature chemical biology Vol. 13; no. 1; pp. 75 - 80
• Main Authors: Piraner, Dan I, Abedi, Mohamad H, Moser, Brittany A, Lee-Gosselin, Audrey, Shapiro, Mikhail G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2017; Nature Publishing Group
• Subjects: 631/326/41; 631/92/469; 631/92/552; 631/92/612/1229; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Bacteria; Bacterial proteins; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry/Food Science; Escherichia coli - genetics; Escherichia coli - isolation & purification; Feces - microbiology; Female; Fever; Gene expression; Gene Expression Regulation, Bacterial; Mice; Microbial Viability; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Skin Diseases - microbiology; Synthetic biology; Temperature; Ultrasonics
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2233

Engineering of temperature-sensitive DNA repressors led to thermal bioswitches, allowing Escherichia coli to respond sharply to temperature at tunable set points and enabling application to host diagnostics and disease therapy. Temperature is a unique input signal that could be used by engineered microbial therapeutics to sense and respond to host conditions or spatially targeted external triggers such as focused ultrasound. To enable these possibilities, we present two families of tunable, orthogonal, temperature-dependent transcriptional repressors providing switch-like control of bacterial gene expression at thresholds spanning the biomedically relevant range of 32–46 °C. We integrate these molecular bioswitches into thermal logic circuits and demonstrate their utility in three in vivo microbial therapy scenarios, including spatially precise activation using focused ultrasound, modulation of activity in response to a host fever, and self-destruction after fecal elimination to prevent environmental escape. This technology provides a critical capability for coupling endogenous or applied thermal signals to cellular function in basic research, biomedical and industrial applications.