Nutrient homeostasis in Acinetobacter baumannii
Lonergan, Zachery Ryan
Zinc is an essential nutrient metal required as a catalytic or structural cofactor for thousands of proteins. During infections, the opportunistic bacterial pathogen Acinetobacter baumannii must acquire zinc and other nutrients from the host. The host attempts to limit nutrients from invading bacterial pathogens, and this metal withholding was visualized during an A. baumannii infection by employing a bioluminescent probe. To circumvent metal withholding, A. baumannii must have mechanisms to compete for essential metals. Transcriptomic and proteomic-based approaches identified several pathways in A. baumannii that may be important for nutrient acquisition. First, A. baumannii induces expression of a predicted metallochaperone named ZigA that contributes to zinc homeostasis. ZigA is also critical for A. baumannii to synthesize sufficient riboflavin levels during zinc starvation. Second, A. baumannii upregulates a cell-wall modifying enzyme named ZrlA. ZrlA aids in A. baumannii cell wall maintenance when nutrient metals are scarce, which also promotes resistance to stressors and the host immune system. Aside from zinc, other nutrients may be acquired from the host by invading bacteria. Analysis of the contents of the extracellular space of the murine lung detected amino acids and other small molecules, suggesting that these may serve as nutrient sources to A. baumannii. Consistent with this, A. baumannii encodes a histidine utilization (Hut) system to metabolize histidine as an energy source. The ammonia-releasing Hut enzyme named HutH is required using histidine as a nitrogen source. A strain lacking hutH is attenuated in a mouse model of A. baumannii pneumonia, which implies histidine serves as a nitrogen source in vivo. Together, this Dissertation identifies key mechanisms employed by the host and A. baumannii to maintain nutrient homeostasis in the context of infection.