Abstract
Quorum sensing is a promising target for next-generation anti-infectives designed to address evolving bacterial drug resistance. The autoinducer-2 (AI-2) is a key quorum-sensing signal molecule which regulates bacterial group behaviors and is recognized by many Gram-negative and Gram-positive bacteria. Here we report a synthetic mammalian cell-based microbial-control device that detects microbial chemotactic formyl peptides through a formyl peptide sensor (FPS) and responds by releasing AI-2. The microbial-control device was designed by rewiring an artificial receptor-based signaling cascade to a modular biosynthetic AI-2 production platform. Mammalian cells equipped with the microbial-control gene circuit detect formyl peptides secreted from various microbes with high sensitivity and respond with robust AI-2 production, resulting in control of quorum sensing-related behavior of pathogenic Vibrio harveyi and attenuation of biofilm formation by the human pathogen Candida albicans. The ability to manipulate mixed microbial populations through fine-tuning of AI-2 levels may provide opportunities for future anti-infective strategies.
Highlights
IntroductionBy implementing gene circuits that interfere with pathological responses in metabolic and autoimmune diseases or tumor progression, the discipline has paved the way for harnessing therapeutic cell implants in vivo[3]
Quorum sensing is a promising target for next-generation anti-infectives designed to address evolving bacterial drug resistance
For the detection of infection, we focused on cell-surface formyl peptide receptors (FPR)[17] that detect invading pathogens releasing formyl peptides such as N-formylmethionyl-leucyl phenylalanine
Summary
By implementing gene circuits that interfere with pathological responses in metabolic and autoimmune diseases or tumor progression, the discipline has paved the way for harnessing therapeutic cell implants in vivo[3] Such devices can detect the onset of microbial infections by scoring pathogenic markers released from damaged tissue[4]. The increase of autoinducer levels with increasing bacterial population density orchestrates population-wide gene expression through a process called quorum sensing[8] This enables unicellular bacteria to function as a multicellular-like organism, and synchronizes behaviors, such as pathogenicity, motility, biofilm formation, and antibiotic resistance[9,10]. Encapsulation protects the designer cells from the host immune system as well as the host from the designer cells for months[25] and enables continuous oxygen supply by promoting autovascularization[25,26], the connection of the designer cells to the bloodstream of the patient
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