Staphylococcus aureus iron acquisition from transferrin via Hts, Sir, and Sst Original paper

What was studied?

This Infection and Immunity study interrogated Staphylococcus aureusiron acquisition from transferrin, mapping the complementary roles of the staphyloferrin A (SA) and staphyloferrin B (SB) siderophore systems and the catechol-capture transporter SstABCD in accessing transferrin-bound iron and promoting virulence. It highlights Staphylococcus aureus iron acquisition from transferrin, demonstrating its importance. Using defined mutants, the authors tested growth in iron-restricted media supplemented with human serum or human holotransferrin, quantified siderophore output, measured ligand binding of the Sst substrate-binding lipoprotein SstD, and assessed organ colonization in a murine sepsis model. Growth curves in serum and holotransferrin demonstrated that either SA or SB supported proliferation, whereas a double biosynthesis knockout was severely impaired; the corresponding figure on page 4 illustrates these dependencies.

Who was studied?

Experiments involved S. aureus Newman and additional clinical backgrounds including USA300 (LAC), USA400 (MW2), and MSSA476, alongside isogenic deletions in siderophore biosynthesis (sfa, sbn), siderophore transport (htsABC for SA and sirA for SB), and the putative catechol transporter sstABCD. Human serum from healthy donors and purified holotransferrin provided physiologic iron ligands. Thus, Staphylococcus aureus iron acquisition from transferrin was scrutinized in different strains and conditions. For in vivo validation, immunocompetent BALB/c mice were challenged intravenously with wild-type and mutant strains to quantify bacterial burdens in the heart, liver, and kidneys at 96 hours. A Western blot on page 6 confirms SstD expression across laboratory and clinical strains, and figures on pages 6 and 8 summarize catecholamine-rescue phenotypes and organ CFU, respectively.

Most important findings

In human serum or holotransferrin, SA and SB functioned as partially redundant systems to extract iron from transferrin, enabling robust growth of single-biosynthesis mutants while the sfa sbn double mutant failed to proliferate; see the growth curves on page 4. Staphylococcus aureus iron acquisition from transferrin was further demonstrated through catecholamine stress hormones, which rescue growth under certain conditions. Catecholamine stress hormones (norepinephrine, epinephrine, dopamine, L-DOPA) at 50 to 200 μM did not augment the growth of the siderophore-proficient wild type but rescued the growth of the siderophore-deficient strain in serum or holotransferrin. This rescue required SstABCD; triple mutants lacking SA/SB plus sst lost catecholamine-mediated growth stimulation, and complementation restored it, as shown on page 6. Beyond catecholamines, S. aureus exploited exogenous catechol-type siderophores: plate bioassays showed utilization of enterobactin, salmochelin S4, petrobactin, bacillibactin, and 2,3-dihydroxybenzoate, with Sst essential for most of these activities.

Purified SstD bound ferric catecholamines and catechol siderophores with low micromolar dissociation constants; Table 2 on page 7 reports Kd values such as ~0.29 μM for enterobactin and ~0.35 μM for salmochelin S4, indicating highest affinity for enteric xenosiderophores. In vivo, single-locus disruptions had modest effects, whereas combined inactivation of siderophore transporters Hts/Sir with Sst yielded the lowest organ burdens, especially in heart and liver; Figure 6 on page 8 depicts these reductions. The study about Staphylococcus aureus iron acquisition from transferrin showed that transport-null strains continued secreting staphyloferrins that they could not re-import, further chelating environmental iron and compounding growth defects, as evidenced by increased CAS-reactive siderophore units on page 8. Hts, Sir, and Sst collectively cooperate to strip iron from transferrin directly via SA/SB or indirectly via catecholamine-liberated or xenosiderophore-bound iron, and their combined loss compromises virulence.

Key implications

Clinically, S. aureus maintains layered, niche-flexible iron scavenging that can subvert transferrin-mediated nutritional immunity. Elevated catecholamines in wound microenvironments or critical illness may inadvertently increase transferrin iron availability to S. aureus through Sst-mediated uptake. This highlights the role of Staphylococcus aureus iron acquisition from transferrin in pathogenesis. For microbiome signatures work, this positions S. aureus in competitive association with enterobactin and salmochelin producers, since SstD can pirate these catecholate ligands, expanding iron access in polymicrobial sites. The high functional importance of HtsA, SirA, and SstD nominates them as vaccine or therapeutic targets that could block iron capture, with the added advantage that transport-null bacteria continue secreting nonutilizable chelators that intensify iron starvation.

Citation

Beasley FC, Marolda CL, Cheung J, Buac S, Heinrichs DE. Staphylococcus aureus Transporters Hts, Sir, and Sst Capture Iron Liberated from Human Transferrin by Staphyloferrin A, Staphyloferrin B, and Catecholamine Stress Hormones, Respectively, and Contribute to Virulence. Infection and Immunity. 2011;79(6):2345-2355. doi:10.1128/IAI.00117-11.