Abrogation of gamma interferon-induced inhibition of Ehrlichia chaffeensis infection in human monocytes with iron-transferrin.
Ehrlichia chaffeensis is an obligate intracellular bacterium which infects cells of the macrophage/monocyte lineage. To test whether gamma interferon (IFN-gamma) inhibits infection of monocytes with E. chaffeensis, human peripheral blood monocytes were incubated with recombinant human IFN-gamma for 3 h and then exposed to E. chaffeensis. With 2,000 U of IFN-gamma per ml, maximal inhibition of infection by E. chaffeensis was observed. THP-1 cells, a human monocyte cell line, pretreated with phorbol myristic acetate or not pretreated, were incubated with various concentrations of IFN-gamma. Maximum inhibition was obtained at 1,000 U of IFN-gamma per ml with phorbol myristic acetate-treated THP-1 cells. However, nontreated cells did not achieve a similar level of anti-ehrlichial activity even with 10,000 U of IFN-gamma per ml. IFN-gamma given within 6 h postinfection was effective in inhibiting E. chaffeensis. Nitric oxide production was not demonstrated in the monocyte medium incubated with IFN-gamma and E. chaffeensis. None of the reactive oxygen intermediate scavengers tested blocked the IFN-gamma-induced anti-ehrlichial activity. Deferoxamine, an intracellular iron chelator, at 15 microM completely inhibited the survival of E. chaffeensis. Iron-saturated transferrin at 1.67 mg/ml completely reversed the IFN-gamma-induced ehrlichial killing. These results indicate that (i) E. chaffeensis is sensitive to intracytoplasmic iron depletion, (ii) E. chaffeensis is sensitive to IFN-gamma-induced killing, and (iii) the anti-ehrlichial activity induced in human monocytes by IFN-gamma is mediated by limitation of available cytoplasmic iron and is not due to the generation of reactive oxygen intermediates or nitric oxide.
Barnewall
R E
RE
Department of Veterinary Pathobiology, College of Veterinary Medicine, Columbus, Ohio 43210-1092.
Rikihisa
Y
Y
D001059:Apoproteins / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D018469:Ehrlichia chaffeensis / Q000254:growth & development*; D016873:Ehrlichiosis / Q000503:physiopathology*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007501:Iron / Q000008:administration & dosage; D009000:Monocytes / Q000382:microbiology*; D011994:Recombinant Proteins; D014168:Transferrin / Q000494:pharmacology*
D001059:Apoproteins; D005609:Free Radicals; D011994:Recombinant Proteins; D014168:Transferrin; C028284:apotransferrin; D007371:Interferon-gamma; D007501:Iron; D003676:Deferoxamine