IsdH binding to hemoglobin:haptoglobin is decoupled from iron acquisition in Staphylococcus aureus

Staphylococcus aureus requires iron for proliferation during infection and acquires it mainly from host hemoglobin (Hb) through the iron-regulated surface determinant (Isd) system. The hemophores IsdB and IsdH mediate the initial steps of Hb recognition. Notably, IsdH also recognizes the hemoglobin:haptoglobin (HbHp) complex, although the molecular determinants and physiological relevance of this interaction remain unclear. Here, combining cryo-electron microscopy and biochemical and cellular assays, we define the basis of HbHp recognition by IsdH. The structure reveals how IsdH engages HbHp and captures the intrinsic conformational flexibility of the HbHp assembly. Functional analyses demonstrate that, despite retaining the ability to extract heme from HbHp, IsdH does not support S. aureus growth under iron-restricted conditions when HbHp is the sole iron source. These findings suggest that HbHp recognition by IsdH may serve functions beyond nutrient iron acquisition, contributing to modulation of host-pathogen interactions.