Role of Iron in Nramp1-Mediated Inhibition of Mycobacterial Growth

Innate resistance to mycobacterial growth is mediated by a gene, Nramp1. We have previously reported that Nramp1 mRNA from macrophages of Mycobacterium bovis BCG-resistant (Bcg(r)) mice is more stable than Nramp1 mRNA from macrophages of BCG-susceptible (Bcg(s)) mice. Based on these observations and on reports that show that the closely related Nramp2 gene is a metal ion transporter, we evaluated the effect of iron on the growth of Mycobacterium avium within macrophages as well as on the stability of Nramp1 mRNA. The addition of iron to macrophages from Bcg(s) mice resulted in a stimulation of mycobacterial growth. In contrast, iron increased the capacity of macrophages from Bcg(r) mice to control the growth of M. avium. When we treated recombinant gamma interferon (IFN-γ)-activated macrophages with iron, we found that iron abrogated the growth inhibitory effect of IFN-γ-activated macrophages from Bcg(s) mice but that it did not affect the capacity of macrophages from Bcg(r) mice to control microbial growth. A more detailed examination of the effect of iron on microbial growth showed that the addition of small quantities of iron to resident macrophages from Bcg(r) mice stimulated antimicrobial activity within a very narrow dose range. The effect of iron on the growth inhibitory activity of macrophages from Bcg(r) mice was abrogated by the addition of catalase or mannitol to the culture medium. These results are consistent with an Fe(II)-mediated stimulation of the Fenton/Haber-Weiss reaction and hydroxyl radical-mediated inhibition of mycobacterial growth.