The Role of the Pseudomonas aeruginosa Heme Metabolites Biliverdin IXβ and IXδ in Pathogenesis and Infection.

Pseudomonas aeruginosa utilizes heme as a major source of iron in the host. The transition to chronic infection coincides with the switch from iron-siderophore uptake to heme utilization. We have shown that the bacterial heme metabolites BVIXβ and BVIXδ are signaling molecules in lifestyle adaptations associated with chronic infection. Herein, we show that allelic strains lacking a functional HemO (hemOin), or one reengineered to produce only BVIXα (hemOα), are significantly attenuated in an acute mouse lung model. The lung bacterial proteome for the allelic strains compared to PAO1 WT infection revealed a significant downregulation in protein translation and central metabolism, suggesting a remodeling of gene expression to maintain essential biosynthetic pathways. However, their respective profiles following infection showed distinct adaptive responses not evident prior to exposure to the mouse lung. In addition to the in-common repression of the TFP chemosensory systems, protein translation, and quorum sensing, the hemOα strain revealed a significant nutrient stress response with upregulation in primary metabolism and flagellum-dependent chemotaxis. In contrast, the hemOin strain showed an oxidative stress response with a dampening in biofilm formation and Type VI secretion and upregulation in quorum sensing and DNA damage repair. Interestingly, the host proteome following infection with the hemO allelic strains compared to PAO1 WT showed an increase in adaptive immunity, lysosomal trafficking proteins, and a reduction in inflammatory response proteins consistent with the reduced bacterial loads. The data herein provides further evidence of the central role heme metabolism plays in the lifestyle adaptation of P. aeruginosa in the host.