The role of serum albumin in <i>Candida albicans</i> filamentation, germ tube formation, and farnesol sequestration

<i>Candida albicans</i> is an opportunistic pathogen and colonizer of the human gut and mucosal membranes. <i>C. albicans</i> exhibits morphological plasticity, which is crucial for its fitness within the host and virulence. Morphogenesis in <i>C. albicans</i> is regulated, in part, by its production of farnesol, an autoregulatory molecule that inhibits filamentation. Morphogenesis is also regulated in response to external cues, such as serum, which stimulates hyphal formation by <i>C. albicans</i>. The precise mechanism by which serum stimulates hyphal formation is unknown. The most abundant serum protein is albumin. The binding affinity of albumin for nonpolar, fatty-acid-like molecules suggests that it may interact directly with exogenous farnesol and influence morphogenesis through sequestration of free farnesol. To test this hypothesis, we assessed whether albumin and albumin devoid of fatty acids (i) stimulated farnesol secretion and (ii) influenced the farnesol threshold required to inhibit filamentation. We found that albumin promoted farnesol secretion and filamentation, and the extent of its ability to do so was based on the presence or absence of bound fatty acids. We hypothesize that albumin not bound to fatty acids has the capacity to bind to farnesol and sequester it from <i>C. albicans</i>, encouraging filamentation.IMPORTANCEFor at least 50 years, researchers have wondered about the mechanisms by which serum stimulates germ tube formation (GTF) and hyphal growth in <i>C. albicans</i>. Here, we tested a model (Nickerson et al., Microbiol Mol Biol Rev 88:e00081-22, 2024, https://doi.org/10.1128/mmbr.00081-22) that serum promotes GTF and farnesol synthesis in part by extracting internal farnesol (F_i) from the cells toward the excess binding capacity of the albumins. The data presented here suggests that albumin not bound by fatty acids sequesters free farnesol thereby modulating filamentation and farnesol secretion by altering the equilibrium of internal vs external farnesol. We expect that the influence of secreted farnesol on cell morphology will differ during pathogenesis depending on location within the body, but sequestration of farnesol in the blood could mediate immune cell recruitment and promote hyphal formation.