Contribution of Active Iron Uptake to Acinetobacter baumannii Pathogenicity

Abstract

<i>Acinetobacter baumannii</i> is an important nosocomial pathogen. Mechanisms that allow <i>A. baumannii</i> to cause human infection are still poorly understood. Iron is an essential nutrient for bacterial growth <i>in vivo</i>, and the multiplicity of iron uptake systems in <i>A. baumannii</i> suggests that iron acquisition contributes to the ability of <i>A. baumannii</i> to cause infection. In Gram-negative bacteria, active transport of ferrisiderophores and heme relies on the conserved TonB-ExbB-ExbD energy-transducing complex, while active uptake of ferrous iron is mediated by the Feo system. The <i>A. baumannii</i> genome invariably contains three <i>tonB</i> genes (<i>tonB1</i>, <i>tonB2</i>, and <i>tonB3</i>), whose role in iron uptake is poorly understood. Here, we generated <i>A. baumannii</i> mutants with knockout mutations in the <i>feo</i> and/or <i>tonB</i> gene. We report that <i>tonB3</i> is essential for <i>A. baumannii</i> growth under iron-limiting conditions, whereas <i>tonB1</i>, <i>tonB2</i>, and <i>feoB</i> appear to be dispensable for ferric iron uptake. <i>tonB3</i> deletion resulted in reduced intracellular iron content despite siderophore overproduction, supporting a key role of TonB3 in iron uptake. In contrast to the case for <i>tonB1</i> and <i>tonB2</i>, the promoters of <i>tonB3</i> and <i>feo</i> contain functional Fur boxes and are upregulated in iron-poor media. Both TonB3 and Feo systems are required for growth in complement-free human serum and contribute to resistance to the bactericidal activity of normal human serum, but only TonB3 appears to be essential for virulence in insect and mouse models of infection. Our findings highlight a central role of the TonB3 system for <i>A. baumannii</i> pathogenicity. Hence, TonB3 represents a promising target for novel antibacterial therapies and for the generation of attenuated vaccine strains.