Mechanisms of Bacterial Lysis Sensing

Matrix-encapsulated communities of bacteria, called biofilms, are ubiquitous in the environment and are notoriously difficult to eliminate in clinical and industrial settings. Existing within biofilms offers resident cells protection from threats, such as bacteriophage attacks, phagocytosis by the host immune system, and antibiotic treatment. However, the fundamental principles by which bacteria gauge environmental threats to inform biofilm development remain unclear. Recently, my laboratory discovered a novel, threat- agnostic mechanism, by which bacteria sense endangerment and respond by forming protective biofilms. The underlying mechanism is a process we call “lysis sensing,” whereby surviving cells sense a signal released during the death of related species and, in turn, initiate biofilm formation. Going forward, the overarching goal of our research program is to develop a comprehensive understanding of lysis sensing across scales, from molecular mechanisms to population-level dynamics. To realize this vision, we will leverage a multidisciplinary approach, involving molecular microbiology, biochemistry, microscopy, computation, and automation. To reveal how lysis-sensing receptors connect threat assessment to the formation of protective biofilms, we will biochemically characterize the Vibrio cholerae lysis-sensing receptor-signal complex that we recently uncovered. To determine how lysis signaling functions in conditions that approximate microbiomes, we will combine experimental and theoretical approaches to examine lysis sensing in homogeneous, spatially structured, and multi-species communities. To assess the pervasiveness and diversity of lysis sensing, we will identify lysis-sensing pathways in additional clinically relevant bacteria using high-throughput imaging approaches that we have pioneered, and we will follow up to uncover underlying molecular mechanisms. Finally, we will extend our studies beyond regulation of the biofilm lifecycle to explore other defense mechanisms activated by bacteria in response to lysis signals. Together, this work will shed light on fundamental concepts by which bacteria undergo threat assessment to respond to the ongoing challenges faced in their host and environmental niches. Our research could uncover new strategies for manipulating microbial behaviors in health and disease, with potential long-term applications for biocontrol, therapeutics, and microbial ecology. Project Number: 1R35GM160020-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Andrew Bridges | Institution: CARNEGIE-MELLON UNIVERSITY, PITTSBURGH, PA | Award Amount: $417,450 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - F Study Section[MRAF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11200844