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- All Subjects: Respiration
- Creators: Bean, Heather
- Creators: Glenberg, Arthur M.
Description
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the 10th leading cause of death, worldwide. The prevalence of drug-resistant clinical isolates and the paucity of newly-approved antituberculosis drugs impedes the successful eradication of Mtb. Bacteria commonly use two-component systems (TCS) to sense their environment and genetically modulate adaptive responses. The prrAB TCS is essential in Mtb, thus representing an auspicious drug target; however, the inability to generate an Mtb ΔprrAB mutant complicates investigating how this TCS contributes to pathogenesis. Mycobacterium smegmatis, a commonly used M. tuberculosis genetic surrogate was used here. This work shows that prrAB is not essential in M. smegmatis. During ammonium stress, the ΔprrAB mutant excessively accumulates triacylglycerol lipids, a phenotype associated with M. tuberculosis dormancy and chronic infection. Additionally, triacylglycerol biosynthetic genes were induced in the ΔprrAB mutant relative to the wild-type and complementation strains during ammonium stress. Next, RNA-seq was used to define the M. smegmatis PrrAB regulon. PrrAB regulates genes participating in respiration, metabolism, redox balance, and oxidative phosphorylation. The M. smegmatis ΔprrAB mutant is compromised for growth under hypoxia, is hypersensitive to cyanide, and fails to induce high-affinity respiratory genes during hypoxia. Furthermore, PrrAB positively regulates the hypoxia-responsive dosR TCS response regulator, potentially explaining the hypoxia-mediated growth defects in the ΔprrAB mutant. Despite inducing genes encoding the F1F0 ATP synthase, the ΔprrAB mutant accumulates significantly less ATP during aerobic, exponential growth compared to the wild-type and complementation strains. Finally, the M. smegmatis ΔprrAB mutant exhibited growth impairment in media containing gluconeogenic carbon sources. M. tuberculosis mutants unable to utilize these substrates fail to establish chronic infection, suggesting that PrrAB may regulate Mtb central carbon metabolism in response to chronic infection. In conclusion, 1) prrAB is not universally essential in mycobacteria; 2) M. smegmatis PrrAB regulates genetic responsiveness to nutrient and oxygen stress; and 3) PrrAB may provide feed-forward control of the DosRS TCS and dormancy phenotypes. The data generated in these studies provide insight into the mycobacterial PrrAB TCS transcriptional regulon, PrrAB essentiality in Mtb, and how PrrAB may mediate stresses encountered by Mtb during the transition to chronic infection.
ContributorsMaarsingh, Jason (Author) / Haydel, Shelley E (Thesis advisor) / Roland, Kenneth (Committee member) / Sandrin, Todd (Committee member) / Bean, Heather (Committee member) / Arizona State University (Publisher)
Created2019
Description
Motor-respiratory coordination is the synchronization of movement and breathing during exercise. The relation between movement and breathing can be described using relative phase, a measure of the location in the movement cycle relative to the location in the breathing cycle. Stability in that relative phase relation has been identified as important for aerobic efficiency. However, performance can be overly attracted to stable relative phases, preventing the performance or learning of more complex patterns. Little research exists on relative phase dynamics in motor-respiratory coordination, although those observations underscore the importance of learning more. In contrast, there is an extensive literature on relative phase dynamics in interlimb coordination. The accuracy and stability of different relative phases, transitions between patterns, and asymmetries between components are well understood. Theoretically, motor-respiratory and interlimb coordination may share dynamical properties that operate in their different physiological substrates. An existing model of relative phase dynamics in interlimb coordination, the Haken, Kelso, Bunz model, was used to gain an understanding of relative phase dynamics in the less-researched motor-respiratory coordination. Experiments 1 and 2 were designed to examine the interaction of frequency asymmetries between movement and breathing with relative phase and frequency, respectively. In Experiment 3, relative phase stability and transitions in motor-respiratory coordination were explored. Perceptual constraints on differences in stability were investigated in Experiment 4. Across experiments, contributions relevant to questions of coordinative variability were made using a dynamical method called cross recurrence quantification analysis. Results showed much consistency with predictions from an asymmetric extension of the Haken, Kelso, Bunz model and theoretical interpretation in the interlimb coordination literature, including phase wandering, intermittency, and an interdependence of perception and action. There were, however, notable exceptions that indicated stability can decrease with more natural frequency asymmetries and the connection of cross recurrence measures to categories of variability needs further clarification. The complex relative phase dynamics displayed in this study suggest that movement and breathing are softly-assembled by functional constraints and indicate that motor-respiratory coordination is a self-organized system.
ContributorsHessler, Eric Edward (Author) / Amazeen, Polemnia G (Thesis advisor) / Amazeen, Eric L (Committee member) / Glenberg, Arthur M. (Committee member) / Gray, Rob (Committee member) / Arizona State University (Publisher)
Created2010