Bacteria adapt to changing environments in complex ways, for example by changing their programs of gene expression and by modifying or degrading proteins. Such regulatory events are vital for the survival of pathogens in the human body and their understanding is fundamental to both the control of infectious diseases and for our understanding of biology. The bacterium Bacillus subtilis is an important model organism, which continues to be intensively studied in a number of laboratories and which has contributed in important ways to the investigation of gene regulation. In particular, this organism undergoes a number of developmental adaptations to stress, including the activation of its ability to be transformed by environmental DNA, the formation of biofilms and of resistant spores. These adaptations involve "decision making", and indeed a single B. subtilis culture contains cells that have undergone transitions to each of these states. This cell-type heterogeneity is probably for bet-hedging in the face of a changeable environment. Each of the developmental states mentioned above is relevant for public health. Transformation is important for the transfer of antibiotic resistance and virulence genes between bacteria, biofilms are of medical importance because some pathogens form biofilms in the human body, for example on in-dwelling catheters and sporulation is an essential part of the life cycle of the causative agent of anthrax and of clostridia, which causes tetanus. The present application concerns several of the most important mechanisms that regulate the transitions of a single cell to each of these adaptive states. Although this choice is random, the likelihood of each transition is highly regulated and dependent on environmental conditions. We will explore a number of transcription factors that are known to influence these likelihoods as well as the role of protein modification. We will place emphasis on the interrelationships among these adaptations, for example asking how cells become transformable in the context of biofilm formation. The logic of the signaling network that governs expression of the various adaptive states will be studied and the relevant molecular interactions will be investigated using genetic, biochemical, cell biological and genomic approaches. We will focus attention on the acetylation of several key proteins, the regulation of protein degradation and the control of protein phosphorylation as regulatory events.
The proposed work will investigate fundamental regulatory mechanisms using the model bacterium Bacillus subtilis, including the process that enables the transfer of virulence and antibiotic resistance genes between bacteria, the formation of biofilms, which in many bacteria is essential for pathogenicity and the formation of resistant spores.
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