Theoretical investigation of biofilm detachment and protection from killing using a bacterium level automata model
Hunt, Stephen Michael.
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This dissertation presents a three-dimensional dynamic, stochastic computer model of biofilm development, BacLAB, created to theoretically explore conjectures associated with biofilms. BacLAB simulates the life cycle of a biofilm by mimicking the physical and biological behavior of a system with a simple set of experimentally determined "rules" applied to the smallest possible biofilm unit (the cell). These rules, however, lead to patterns on a larger scale. Much as bacterial cells organize themselves in a biofilm as a response to individual spatial conditions, the resulting model structure is produced in a process of self-organization rather than by some predetermined plan for biofilm development. Detachment of cells from a mature biofilm is an important process determining the accumulation of attached cells and allowing for dissemination of the organism. The mode by which cells detach is, therefore, a critical stage in the life cycle of biofilms. Initial simulation studies with BacLAB were used to investigate conjectures associated with detachment resulting from either the accumulation of a metabolic product or the depletion of a metabolic substrate. Results demonstrated that the typical simulated biofilm eventually attains a steady state where biofilm growth was counterbalanced by detachment with cell areal densities comparable to those in laboratory biofilms. Some of the phenomena predicted by BacLAB include sloughing, hollow cell clusters and gradients in solute concentration and growth rate. BacLAB was also adapted to simulate the protection from killing by antimicrobial agents afforded to microorganisms in the biofilm state. It is believed that the reduced susceptibility of bacteria in biofilms is an important factor in the persistence of some chronic infections and the mechanisms of protection are only moderately understood. Because antimicrobials are thought be more effective in killing actively growing bacteria, the rate of killing was assumed to be proportional to the local concentration of the substrate. The results suggest that substrate limitation has the potential to contribute to the reduced antimicrobial susceptibility found in biofilms, but is not adequate by itself in explaining the log-term persistence of biofilm viability observed experimentally.