Iron Acquisition by Bacteria
Since heme is one the most abundant sources of iron in any mammalian host, many microorganisms have also evolved mechanisms to utilize heme, hemoglobin, or the hemopexin-heme complex as a source of iron. Pathogens can acquire heme either by direct uptake or by heme-scavenging proteins known as hemophores.
Direct uptake involves the binding of heme or heme proteins to specific outer membrane (OM) receptors. Subsequently, heme is removed from the bacterial receptor and transported into the cell by a process that is energy dependent. The TonB-ExbB-ExbD system generates the proton-motive force required for transport in both Gram-positive and Gram-negative bacteria (Genco and Dixon 2001). Alternatively, uptake may occur by means of secreted heme-binding proteins known as hemophores. These molecules function in a manner analogous to siderophores where heme is withdrawn from host proteins and the hemophore- heme complex is docked back onto the bacterial surface. Heme is trafficked into the cell by specific transporters and heme-associated iron is then released in the cytoplasm. Gram-negative organisms can utilize either one or both of the above mechanisms to obtain iron (Cassat and Skaar 2013). For example, P aeruginosa can obtain heme by direct uptake as well as hemophore-mediated uptake (Cornelis 2010). On the other hand, Gram-positive bacteria commonly acquire iron by the direct uptake of heme; an example is the human pathogen S. aureus which preferentially acquires iron by the direct uptake of heme (Skaar et al. 2004). In addition, certain Gram-negative species such as P. gingivalis and E. coli also utilize proteases that degrade hemoglobin, resulting in the release and uptake of heme (Otto et al. 1998; DeCarlo et al. 1999; Lewis et al. 1999).