Transferrin, Iron, and Serum Lipids Enhance or Inhibit Mycobacterium avium Replication in Human Macrophages

Abstract

Mycobacterium avium grows exponentially over 7 days in human macrophages when they are cultured in serumless medium. Normal serum inhibits this replication. When serum lipids were extracted using chloroform, the inhibitor was present in the lipid-free component. The lipid extract significantly enhanced M. avium replication. Iron (Fe2+) added at 8-80 micrograms/mL to infected macrophage cultures in serum resulted in enhanced mycobacterial replication. Serum-induced inhibition of bacterial growth in serumless medium could be duplicated with apotransferrin at 50-500 micrograms/mL. At 1000 micrograms/mL, apotransferrin no longer inhibited bacterial growth. Holotransferrin was not inhibitory, and at 500 micrograms/mL, it enhanced M. avium growth. Depletion of the transferrin in serum by affinity chromatography using goat anti-transferrin on protein G-Sepharose removed inhibitory activity. These results indicate that transferrin levels, transferrin saturation, iron levels, and serum lipids can profoundly alter the replication of M. avium in association with macrophages.

Iron Storage Proteins Are Essential for the Survival and Pathogenesis of Mycobacterium tuberculosis in THP-1 Macrophages and the Guinea Pig Model of Infection

“…Since BfrA and BfrB are the only two iron storage proteins in M. tuberculosis, their absence perhaps results in the insufficient supply of iron to the cell, leading to the concomitant attenuation of growth. The attenuation of M. tuberculosis growth in macrophages in response to the deficiency of iron in host macrophages has been reported earlier in several studies (9,11).…”

Tumor necrosis factor alpha (TNFalpha) promotes growth of virulent Mycobacterium tuberculosis in human monocytes iron-mediated growth suppression is correlated with decreased release of TNFalpha from iron-treated infected monocytes.

“…L. pneumophila and E. chaffeensis are sensitive to intracellular iron deprivation, and as a consequence, alterations in human monocyte iron metabolism induced by IFN␥ will influence their growth (1,2,7). In a fashion similar to L. pneumophila, intracellular iron dependence in mononuclear phagocytes has been demonstrated for Francisella tularensis (3,8), and iron has been found to have a permissive effect on the intracellular growth of Mycobacterium avium intracellulare (5). In contrast, iron has been found to have both positive and negative effects on intracellular growth of Listeria monocytogenes depending on intracellular iron concentrations, and a negative effect on intracellular growth of Brucella abortus.…”

“…Iron has been shown to enhance, and in some cases suppress, the growth of various intracellular bacterial pathogens (1)(2)(3)(4)(5)(6)(7)(8). The availability of intracellular iron to these pathogens can be influenced by cytokines (1,7,9).…”

Mycobacterium tuberculosis acquires iron by cell-surface sequestration and internalization of human holo-transferrin

“…Another recent study demonstrates that the recombinant BCG(mbtB)30 strain which is unable to synthesize both mycobactin and carboxymycobactin retains the ability to multiply and survive within macrophages over the initial days of infection 14 . The importance of transferrin in mycobacterial iron acquisition is also evident from studies demonstrating that intraphagosomal M.tb siderophore knockout strains retained the ability to recruit and acquire iron by utilizing transferrin 5,14,15 . Other studies have demonstrated that ironsaturated transferrin promotes the replication of M. avium within the phagosome 15 .…”

“…The importance of transferrin in mycobacterial iron acquisition is also evident from studies demonstrating that intraphagosomal M.tb siderophore knockout strains retained the ability to recruit and acquire iron by utilizing transferrin 5,14,15 . Other studies have demonstrated that ironsaturated transferrin promotes the replication of M. avium within the phagosome 15 . Elevated serum iron and high levels of ironsaturated transferrin are known to have a strong correlation with the exacerbation of tuberculosis in both mouse models and patient studies 3,[16][17][18][19][20] .…”