Transferrin-Dependent Growth Inhibition of Yeast-Phase Histoplasma capsulatum by Human Serum and Lymph

Abstract

Nonspecific host defense mechanisms that may limit growth of yeast-phase Histoplasma capsulatum in vivo were examined using an in vitro system of cell-free liquid culture. Native human transferrin in serum and lymph, or purified transferrin added to serumfree medium, inhibited yeast replication 10- to 50-fold. Supplementation of serum with iron to complete or almost complete saturation of total iron-binding capacity neutralized inhibition. Substitution of Zn++, Mn++, or Cu++ for Fe++ did not affect inhibition. Neither complement nor antibody was a relevant factor. Results of culture in medium with unsaturated transferrin followed by replenishment with iron indicated that iron deprivation was either fungistatic or fungicidal, depending on the yeast strain and, in serum-free medium, on the iron content of transferrin. Transferrin-dependent fungistasis was associated with morphologic alteration of yeasts as determined by electron microscopy. Thus, susceptibility of yeast-phase H. capsulatum to iron starvation by unsaturated transferrin may contribute to their low virulence in vivo.