The Exploitation of Host Iron Sources by Candida albicans during Oral Infection
Tight binding of iron by host proteins provides a natural resistance to microbial infections described as “nutritional immunity”. Inside oral epithelial cells, iron is stored in ferritin. The aim of this study was to determine the natural iron sources for the human pathogenic fungus Candida albicans during oral infection. In vitro, C. albicans can grow at physiological pH with ferritin as the sole source of iron while the baker’s yeast Saccharomyces cerevisiae cannot. Moreover, C. albicans is only able to use ferritin as an iron source under conditions which permit acid production and acidification of the surrounding environment. A screen of mutants lacking components of each of the three iron acquisition systems of C. albicans revealed that only the reductive pathway is involved in ferritin iron utilisation. Additionally, hyphae but not yeast cells of this fungus can bind ferritin and this binding is essential for iron acquisition from ferritin. Transcriptional analysis of C. albicans cells binding ferritin suggested a role for the hyphal-associated protein Als3p in binding of ferritin. Indeed, hyphae of a mutant lacking Als3p were unable to bind ferritin. Furthermore, heterologous expression of Als3p allowed S. cerevisiae to bind ferritin, suggesting that Als3p is a ferritin receptor. Immunofluorescence localisation of ferritin in epithelial cells infected with C. albicans showed ferritin surrounding hyphae from wild type but not Dals3 mutant cells. In summary, this study suggests that C. albicans can use ferritin as an iron source via direct binding by Als3 on the surface of hyphae; iron release is then mediated by acidification and uptake is facilitated by the reductive pathway. This is the first study which demonstrates that a pathogenic microbe can directly use ferritin as an iron source.