Human serum albumin promotes heme-iron utilization by fungi

A large part of biological iron is found as an iron-protoporphyrin IX complex, or heme. In the human host environment, which is exceptionally poor in free iron, heme iron, particularly from hemoglobin, constitutes a major iron source for invading microbial pathogens. Several fungi were shown to utilize free hemin and Candida albicans, a major opportunistic pathogen, is able to either utilize free hemin or extract it from hemoglobin. Human serum albumin (HSA) is the main scavenger of free hemin in the blood. Tight binding of hemin by HSA restricts its toxic chemical reactivity, and could restrict its availability as iron source for potential pathogens. Surprisingly, we find that HSA greatly increases availability of hemin as iron source for C. albicans. Utilization of albumin-bound hemin requires the same hemophore cascade system that mediates hemoglobin-iron utilization. Accordingly, we find that purified C. albicans hemophores are able to extract hemin bound to albumin. Since many common drugs are known to bind to HSA, we tested whether they could interfere with heme-iron utilization. We show that utilization of albumin-bound hemin by C. albicans can be inhibited by therapeutic concentrations of the anti-inflammatory drugs naproxen and salicylic acid.