Stress sensing and processing by bacterial cytoplasmic megacomplexes

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PROJECT SUMMARY Bacteria can grow and divide in a remarkably wide range of quickly changing environments, adapting to harsh conditions by sensing external stressors and applying that information to mount an appropriate response. Stress- sensing processes are relevant to human health: pathogenic bacteria with activated stress responses are less susceptible to many antimicrobial treatments, and nearly 100,000 Americans die each year from infections with drug-resistant bacteria. Indeed, environmental antibiotics are one stressor (among many) to which bacterial cells readily respond. A persistent challenge has been that, although the molecular components of the environmental stress response system are well known, little has been discovered about the dynamics of these stress responses over time, particularly in individual cells. The PI has combined bacterial genetics with microfluidic technology to directly observe the responses of single-cell lineages under tightly controlled environmental stress conditions, revealing that the stress-response system is capable of eliciting several distinct responses with different dynamics that depend on which stress sensors are present in the cell. These results raise additional fundamental questions. How do stress-sensing proteins located in the cytoplasm effectively respond to the onset of stressors that are outside the cell? Which molecular features of stress-response proteins specify the stressors they respond to and the dynamic response patterns they instigate? How do different dynamic stress-response patterns contribute to cellular fitness and survival in adverse conditions? The proposed studies tackle these questions by taking advantage of the bacterium Bacillus subtilis as a highly tractable model for environmental stress. By bringing together classical bacterial genetics, molecular techniques, fluorescence microscopy, and microfluidic technology, these studies will yield a new and more mechanistic understanding of the principles that govern how bacterial cells sense environmental stress, process those sensory inputs, and produce an effective response. The results will have broad implications for understanding the general features of stress responses across many biological systems. They will also furnish knowledge that will be useful for devising antimicrobial treatment strategies that interfere with environmental stress sensing.