Abstract
Bordetella pertussis and Bordetella bronchiseptica are capable of obtaining iron from hemin and hemoglobin. Genes encoding a putative bacterial heme iron acquisition system (bhu, for Bordetella heme utilization) were identified in a B. pertussis genomic sequence database, and the corresponding DNA was isolated from a virulent strain of B. pertussis. A B. pertussis bhuR mutant, predicted to lack the heme outer membrane receptor, was generated by allelic exchange. In contrast to the wild-type strain, bhuR mutant PM5 was incapable of acquiring iron from hemin and hemoglobin; genetic complementation of PM5 with the cloned bhuRSTUV genes restored heme utilization to wild-type levels. In parallel studies, B. bronchiseptica bhu sequences were also identified and a B. bronchiseptica bhuR mutant was constructed and confirmed to be defective in heme iron acquisition. The wild-type B. bronchiseptica parent strain grown under low-iron conditions produced the presumptive BhuR protein, which was absent in the bhuR mutant. Furthermore, production of BhuR by iron-starved B. bronchiseptica was markedly enhanced by culture in hemin-supplemented medium, suggesting that these organisms sense and respond to heme in the environment. Analysis of the genetic region upstream of the bhu cluster identified open reading frames predicted to encode homologs of the Escherichia coli ferric citrate uptake regulators FecI and FecR. These putative Bordetella regulators may mediate heme-responsive positive transcriptional control of the bhu genes.
Highlights
Pathogenic microorganisms encounter severe iron limitation in mammalian hosts, where the concentration of free iron is several orders of magnitude less than that required to support microbial growth [18]
We identified a cluster of B. pertussis genes predicted to encode proteins highly similar to those of bacterial heme iron acquisition systems with single-component TonB-dependent outer membrane receptors
PhuR was selected as a representative TonB-dependent heme outer membrane receptor, in part because a BLASTP database search revealed that it was highly similar to heme receptors of several gram-negative bacterial species [57]
Summary
Pathogenic microorganisms encounter severe iron limitation in mammalian hosts, where the concentration of free iron is several orders of magnitude less than that required to support microbial growth [18]. In response to iron starvation, they produce the macrocyclic dihydroxamate siderophore alcaligin [15, 53] and use a variety of heterologous siderophores, including enterobactin [7], ferrichrome, and desferrioxamine B [6], for iron retrieval These organisms can obtain iron from host sources transferrin [60, 61], lactoferrin [61], heme [1, 55], and hemoglobin [55]. We identified a cluster of B. pertussis genes (designated bhu, for Bordetella heme utilization) predicted to encode proteins highly similar to those of bacterial heme iron acquisition systems with single-component TonB-dependent outer membrane receptors. Nucleotide sequence analysis of the region immediately upstream of the heme utilization gene cluster identified two open reading frames predicted to encode homologs of the Escherichia coli ferric citrate uptake system positive regulators FecI and FecR [11], suggesting that a similar positive regulatory mechanism may exist for the Bordetella heme system
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