Iron is tightly controlled in mammalian tissues and regulates virulence factors in various pathogenic organisms. The influence of Fe availability upon production of cryptococcal capsular polysaccharide was studied. Polysaccharide, measured as cell-bound glucuronyl residues, increased more than threefold as available Fe in the culture medium was varied from repletion to tight sequestration and depletion in five incremental steps. Since physiologic CO2 concentration may serve as stimulus for cryptococcal polysaccharide synthesis, the combined effect of Fe availability and CO2 on encapsulation was studied. Addition of dissolved, loosely chelated Fe moderated the effect of CO2. Tight chelation of dissolved Fe potentiated the CO2 effect. Tissue from infected mice showed heavily encapsulated organisms, consistent with results with physiologic CO2 concentration and Fe deprivation. In conclusion, cryptococcal polysaccharide synthesis is increased by limitation of ferric iron availability to the cell and by dissolved CO2, and the two effects are additive.

The differential effects of iron on the growth of virulent and avirulent Listeria monocytogenes were examined. We found that virulent strains exhibited faster rates of growth as a function of iron than did the avirulent strains. We also noted that serum was microbiostatic, but this microbiostasis was overcome either by saturating the serum transferrin with iron or by increasing the number of organisms initially inoculated into the serum. We were unable to identify any component of a high-affinity iron transport system. We did find, however, that this microorganism removes iron from Fe -transferrin-CO3-- by a reductive pathway, and we propose that this pathway is a nonspecific mechanism of iron acquisition.

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Regulation of iron homeostasis in many pathogens is principally mediated by the ferric uptake regulator, Fur. Since acquisition of iron from the host is essential for the intracellular pathogen Listeria monocytogenes, we predicted the existence of Fur-regulated systems that support infection. We examined the contribution of nine Fur-regulated loci to the pathogenicity of L. monocytogenes in a murine model of infection. While mutating the majority of the genes failed to affect virulence, three mutants exhibited a significantly compromised virulence potential. Most striking was the role of the membrane protein we designate FrvA (Fur regulated virulence factor A; encoded by frvA [lmo0641]), which is absolutely required for the systemic phase of infection in mice and also for virulence in an alternative infection model, the Wax Moth Galleria mellonella. Further analysis of the ΔfrvA mutant revealed poor growth in iron deficient media and inhibition of growth by micromolar concentrations of haem or haemoglobin, a phenotype which may contribute to the attenuated growth of this mutant during infection. Uptake studies indicated that the ΔfrvA mutant is unaffected in the uptake of ferric citrate but demonstrates a significant increase in uptake of haem and haemin. The data suggest a potential role for FrvA as a haem exporter that functions, at least in part, to protect the cell against the potential toxicity of free haem.