Systems biology approaches to mechanisms of bacterial stress adaptation
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Bacteria exhibit highly adaptive behaviors in the face of stress, which poses significant challenges for the eradication of infectious disease as well as for the success of biotechnology efforts to harness microbes as production chassis. Systems biology, which studies interactions between the components of a biological system, presents a framework for using computational strategies to further understand the complexity of bacterial physiology. In this work we use systems biology to elucidate the comprising mechanisms of two facets of bacterial stress adaptation. In the first part of this work, we develop a method to facilitate the characterization of small non-coding RNAs, which are involved in mediating adaptive physiological responses to changing environmental conditions. We implement a network biology approach based on expression profiling to predict the functional and regulatory interactions for small RNAs in Escherichia coli. We experimentally validate functional predictions for three small RNAs in our inferred network and demonstrate that a specific small RNA interacts with a transcription factor in a mutually inhibitory relationship, demonstrating a new cellular regulatory motif in bacteria. In the second part of this work, we investigate the role of phages, viruses which infect bacteria, in the adaptation of the microbiome to stressful environments. Disruption of intestinal homeostasis has been studied at the level of microbial composition; however, investigation of the gut ecosystem has evinced a myriad of resident phages, and it remains unclear how perturbation of the gut environment affects these viral symbionts. Our analysis demonstrates that antibiotic treatment, a prevalent stress for commensal microbes, enriches the phage metagenome for stress-specific and niche-specific functions. We also show that antibiotic treatment expands the interactions between phage and bacterial species, leading to a more highly connected phage-bacterial network for gene exchange. Our work indicates that the adaptive capacity of the phageome may represent a community-based mechanism for protecting the gut microfiora and preserving its functional robustness during antibiotic stress. Systems biology approaches toward understanding bacterial behavior within an environmental and evolutionary context may improve our relationships with microbes, which will be critical in an era where the potential of these organisms remains both promising and incipient.
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