Structural requirements for hemoglobin to induce fibronectin receptor expression in Candida albicans

Hemoglobin (Hb) is a host factor that induces expression of a promiscuous r eceptor on Candida albicans for fibronectin (FN) and several other extracel lular matrix proteins. FN receptor expression was induced by ferric (Hb(+)M et and Hb(+)CN), ferrous (HbCO and HbO(2)), and cobalt-protoporphyrin deriv atives of Hb, whereas globin was inactive. The Hb derivatives all exhibited saturable, dose-dependent kinetics of FN receptor induction, suggesting th at Hb may be acting as a receptor ligand. Soluble Hb bound saturably to a l ow-affinity binding site [K-d = (1.1 +/- 0.2) X 10(-6) M] on C. albicans bl astospores. However, uptake of (55)FeHb revealed that heme or iron transpor t into the cell is not required for induction, since internalization of Fe- 55 from Hb did not occur until after induction of FN binding. The serum Hb- binding protein, haptoglobin, specifically abrogated this response, indicat ing that protein structure rather than the heme ligand or iron is necessary for induction of this signaling pathway. C. albicans also adhered to immob ilized Hb, which was sufficient to induce FN receptor expression, and to Hb polymers that formed in defined Hb liquid media in the presence of cells. Formation of Hb polymers in solution required metabolic energy, since the a ggregation process was halted with azide addition. Collectively, these data demonstrate that C. albicans recognizes polymerized Hb through multivalent low-affinity interactions, and this may be a host environmental cue that t riggers extracellular matrix receptor expression at a septic site.