Molecular mechanisms of Staphylococcus aureus iron acquisition

Abstract

The unique redox potential of iron makes it an ideal cofactor in diverse biochemical reactions. Iron is therefore vital for the growth and proliferation of nearly all organisms, including pathogenic bacteria. Vertebrates sequester excess iron within proteins in order to alleviate toxicity and restrict the amount of free iron available for invading pathogens. Restricting the growth of infectious microorganisms by sequestering essential nutrients is referred to as nutritional immunity. In order to circumvent nutritional immunity, bacterial pathogens have evolved elegant systems that allow for the acquisition of iron during infection. The gram-positive extracellular pathogen Staphylococcus aureus is a commensal organism that can cause severe disease when it gains access to underlying tissues. Iron acquisition is required for S. aureus colonization and subsequent pathogenesis. Herein we review the strategies S. aureus employs to obtain iron through the production of siderophores and the consumption of host heme.

Figure 1. A model of the Staphylococcus aureus iron acquisition pathways

A. S. aureus produces two siderophores, staphyloferrin A and staphyloferrin B. Staphyloferrin A import is mediated by the HtsA lipoprotein and HtsBC permease. The SirA lipoprotein is the receptor for staphyloferrin B and the SirBC permease mediates the translocation of staphyloferrin B across the membrane. S. aureus imports xenosiderophores produced by other bacteria through the binding activity of FhuD1 and FhuD2 receptor lipoproteins and the FhuBG permease. The energy needed for siderophore uptake is provided by the FhuC ATPase. B. Heme acquisition is mediated by the Isd system. IsdH binds hemoglobin-haptoglobin and IsdB binds hemoglobin. Heme is passed through the NEAT domains of IsdH (N1-N3) IsdB (N1-N2), IsdA, and IsdC. Heme can also be passed from IsdH or IsdB directly to the IsdE heme-receptor lipoprotein. Heme transport across the membrane occurs through either the IsdDF or HtsBC permeases. Once in the cytoplasm heme is a substrate for the heme-degrading enzymes IsdG and IsdI. S. aureus degradation of heme leads to the release of iron and the production of staphylobilin. C. Genetic loci involved in S. aureus iron acquisition pathways. The sfa operon encodes the genes required for staphyloferrin A biosynthesis, while the genes within the sbn operon encode the staphyloferrin B synthesis genes. Promoter regions containing a consensus fur box are indicated with an orange oval. Genes are not drawn to scale.

Figure 2. Sensing and alleviation of heme-associated toxicity

HssS senses exposure to heme through an unknown mechanism. This results in the autophosphorylation of HssS which is followed by a phosphorelay between histidine 279 of HssS and aspartate 52 of HssR. Phosphorylated HssR binds to a direct repeat sequence (DR) found within the hrtAB promoter region resulting in the expression of those genes. The HrtA ATPase and the HrtB permease form an ABC-type transport system that alleviates heme-mediated toxicity through an unknown mechanism.