The heme sensor system of Staphylococcus aureus

Abstract

The important human pathogen Staphylococcus aureus is able to satisfy its nutrient iron requirement by acquiring heme from host hemoglobin in the context of infection. However, heme acquisition exposes S. aureus to heme toxicity. In order to detect the presence of toxic levels of exogenous heme, S. aureus is able to sense heme through the heme sensing system (HssRS) two-component system. Upon sensing heme, HssRS directly regulates the expression of the heme-regulated ABC transporter HrtAB, which alleviates heme toxicity. Importantly, the inability to sense or respond to heme alters the virulence of S. aureus, highlighting the importance of heme sensing and detoxification to staphylococcal pathogenesis. Furthermore, potential orthologues of the Hss and Hrt systems are found in many species of Gram-positive bacteria, a possible indication that heme stress is a challenge faced by bacteria whose habitats include host tissues rich in heme.

Fig. 1

Signaling events that connect heme sensing by the HssRS TCS to upregulation of HrtAB and heme detoxification: (1) Heme is imported into the staphylococcal cytoplasm through the actions of the Isd and Hts systems. (2) Heme activates the histidine kinase HssS directly through a receptor-ligand interaction, or indirectly through the heme-mediated accumulation of toxic metabolites. (3) Activation of HssS results in autophosphorylation and (4) transphosphorylation of HssR. (5) Phosphorylated HssR binds to a direct repeat sequence within the hrtAB promoter. (6) This increases the transcription of the hrtAB genes by recruitment of RNA polymerase. (7) Newly synthesized HrtAB alleviates heme toxicity (8) through the export of heme or an unknown molecule that accumulates in the S. aureus cytoplasm upon heme exposure.

Fig. 2

Conservation of HssRS and HrtAB across Gram-positive bacteria. Sequenced bacterial genomes were interrogated for potential orthologues of S. aureus hssRS and hrtAB genes by BLAST analyses. The indicated bacterial strains were found to encode potential Hss/Hrt systems. Boxes indicate open reading frames and point in the direction of transcription. Dark grey boxes: HrtA; light grey boxes: HrtB, empty boxes: HssR, boxes with diagonal lines: HssS; black boxes: non-Hss/Hrt open reading frames (other genes). Numbers within boxes indicate the annotated gene number. Numbers below boxes are percent similarities with respect to the corresponding S. aureus COL Hss/Hrt gene. Percent similarities were calculated at the amino acid level using a Lipman-Pearson Protein Alignment (gap penalty = 4, gap length penalty = 12). Single asterisk denotes large separation between genes; double asterisk denotes that this potential HssR orthologue is split into two open reading frames in the genome of this species.