Defining the systems-level impact of iron limitation in Klebsiella pneumoniae

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The long-term goal of my research program is to understand fundamental mechanisms that allow bacteria to adapt to nutrient limitation. Iron is a critical component of many cellular processes, including DNA replication and oxygen metabolism, as well as a cofactor for many cellular reactions. In Klebsiella pneumoniae, a Gram--negative, encapsulated bacterium, the role of iron and its influence on siderophore expression was recently studied at the transcriptional level, defining a role in inflammation, bacterial dissemination, and hypoxia -inducible factor 1a stabilization during infection. However, at the protein level, the effect of variable iron concentrations has not been well defined. Recently, we discovered that changes in iron availability impact the cellular proteome and secretome of K. pneumoniae. Our proteomic investigation into the role of iron in K. pneumoniae uncovered modulation of a variety of proteins, including those associated with signal transduction pathways (e.g., cAMP receptor and kinases), bacterial cell adhesion (e.g., lipoproteins), polysaccharide capsule production (e.g, capsule export protein), enzymatic activity (e.g., proteases), and homeostasis (e.g., transcription factors). Moreover, disruption of proteins (e.g., Lon protease) influenced by the presence or absence of iron modulate bacterial growth, capsule, and iron utilization. Our work has begun to uncover the diverse impact of iron on cellular processes and regulation in K. pneumoniae, but many questions remain regarding the mechanisms by which iron directly (via transporters or siderophores) or indirectly (via transcriptional regulators, signaling cascades) influences bacterial survival. The overarching hypothesis is that K. pneumoniae alters its proteome in response to changing iron concentrations to modulate a diverse array of cellular processes to promote its survival. For this proposal, I will focus on the connection between iron availability in K. pneumoniae and the regulation of i) signal transduction pathways, ii) enzyme production, and iii) general stress response. Over the next 5 years, my research program will provide novel insight into the diverse role of iron in K. pneumoniae and define the biological mechanisms that underscore bacterial adaptability. This work has important implications for our understanding of the bacterial response to iron, and our findings, along with the approaches used, will transcend prokaryotic cell biology and be applicable to diverse biological systems (e.g., fungal species).