Iron transport systems in Neisseria meningitidis

Abstract

Acquisition of iron and iron complexes has long been recognized as a major determinant in the pathogenesis of Neisseria meningitidis. In this review, high-affinity iron uptake systems, which allow meningococci to utilize the human host proteins transferrin, lactoferrin, hemoglobin, and haptoglobin-hemoglobin as sources of essential iron, are described. Classic features of bacterial iron transport systems, such as regulation by the iron-responsive repressor Fur and TonB-dependent transport activity, are discussed, as well as more specific features of meningococcal iron transport. Our current understanding of how N. meningitidis acquires iron from the human host and the vaccine potentials of various components of these iron transport systems are also reviewed.

FIG. 1.

Schematic representation of iron acquisition systems in N. meningitidis. Under iron-limiting conditions, meningococci express several proteins involved in the uptake and processing of iron and heme. Several of these are outer membrane receptor proteins, which recognize transferrin, lactoferrin, hemoglobin, and hemoglobin-haptoglobin. Depicted are the TonB-dependent receptors, TbpAB, LbpAB, HmbR, and HpuAB. All consist of a pore-forming membrane protein and, except for HmbR, a lipoprotein that is involved in substrate binding. An uncharacterized TonB-independent heme uptake system is not shown. The FbpABC transport proteins are involved in the periplasmic transport of ferric iron, and an undescribed system may exist for the periplasmic transport of heme. In the cytoplasm, ferric iron and heme can be stored in bacterioferritin. Heme can also be converted to biliverdin and CO in the cytoplasm by heme oxygenase. Dimeric forms of TonB and the FbpBC proteins from E. coli have been described but are not depicted as such here. LOS, lipooligosaccharide

FIG. 2.

Topological model of HmbR. The size of each β-sheet was arbitrary taken to be 10 aa residues. L1 through L11 indicate putative surface-exposed loops of HmbR. Numerals indicate amino acid residues of HmbR.

FIG. 3.

Chemical steps in heme degradation as defined by studies of eukaryotic heme oxygenases and C. diphtheriae HmuO.

FIG. 4.

Crystal structure of N. meningitidis heme oxygenase, HemO, with bound heme.