A generic cell-based biosensor converts bacterial infection signals into chemoattractants for immune cells

Abstract Bacterial infection is a major challenge to human health. Although various potent antibiotics have emerged in recent decades, current challenges arise from the increasing number of multi-drug-resistant species. Infections associated with implants represent a particular challenge because they are usually diagnosed at an advanced stage and are difficult to treat with antibiotics owing to the formation of protective biofilms. In this study, we designed and explored a synthetic biology-inspired cell-based biosensor/actor for the detection and counteraction of bacterial infections. The system is generic, as it senses diverse types of infections and acts by enhancing the endogenous immune system. This strategy is based on genetically engineered sensor/actor cells that can sense type I interferons (IFNs), which are released by immune cells at the early stages of infection. IFN signalling activates a synthetic circuit to induce reporter genes with a sensitivity of only 5 pg ml⁻¹ of IFN and leads to a therapeutic protein output of 100 ng ml⁻¹, resulting in theranostic cells that can visualize and fight infections. Robustness and resilience were achieved by implementing a positive feedback loop. We showed that diverse gram-positive and gram-negative implant-associated pathogenic bacteria activate the cascade in co-culture systems in a dose-dependent manner. Finally, we showed that this system can be used to secrete chemoattractants that facilitate the infiltration of immune cells in response to bacterial triggers. Together, the system is not only universal to bacterial infections, but also hypersensitive, allowing the sensing of infections at initial stages.