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© The Rockefeller University Press, 0022-1007/1999/9/717/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 5, September 6, 1999 717-724

Mycobacterium tuberculosis Expresses a Novel pH-dependent Divalent Cation Transporter Belonging to the Nramp Family

Daniel Agranoffa, Irene M. Monahanb, Joseph A. Manganb, Philip D. Butcherb, and Sanjeev Krishnaa
a From the Department of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom
b From the Department of Medical Microbiology, St. George's Hospital Medical School, London SW17 ORE, United Kingdom

Correspondence to: Sanjeev Krishna, Department of Infectious Diseases, St. George's Hospital Medical School, Cranmer Terrace, London SW20 ORE, UK. Tel:181-725-5836 Fax:181-725-3487 E-mail:s.krishna{at}sghms.ac.uk.

Mammalian natural resistance–associated macrophage protein (Nramp) homologues are important determinants of susceptibility to infection by diverse intracellular pathogens including mycobacteria. Eukaryotic Nramp homologues transport divalent cations such as Fe2+, Mn2+, Zn2+, and Cu2+. Mycobacterium tuberculosis and Mycobacterium bovis (bacillus Calmette-Guérin [BCG]) also encode an Nramp homologue (Mramp).

RNA encoding Mramp induces ~20-fold increases in 65Zn2+ and 55Fe2+ uptake when injected into Xenopus laevis oocytes. Transport is dependent on acidic extracellular pH and is maximal between pH 5.5 and 6.5. Mramp-mediated 65Zn2+ and 55Fe2+ transport is abolished by an excess of Mn2+ and Cu2+, confirming that Mramp interacts with a broad range of divalent transition metal cations.

Using semiquantitative reverse transcription PCR, we show that Mramp mRNA levels in M. tuberculosis are upregulated in response to increases in ambient Fe2+ and Cu2+ between <1 and 5 µM concentrations and that this upregulation occurs in parallel with mRNA for y39, a putative metal-transporting P-type ATPase. Using a quantitative ratiometric PCR technique, we demonstrate a fourfold decrease in Mramp/y39 mRNA ratios from organisms grown in 5–70 µM Cu2+. M. bovis BCG cultured axenically and within THP-1 cells also expresses mRNA encoding Mramp.

Mramp exemplifies a novel prokaryotic class of metal ion transporter. Within phagosomes, Mramp and Nramp1 may compete for the same divalent cations, with implications for intracellular survival of mycobacteria.

Key Words: bacillus Calmette-Guérin, Xenopus oocyte, metal ion, phagosome, intracellular pathogen


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