Mycobacterial P1-Type ATPases Mediate Resistance to Zinc Poisoning in Human Macrophages

Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobac...

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Published in:Cell host & microbe 2011-09, Vol.10 (3), p.248-259
Main Authors: Botella, Hélène, Peyron, Pascale, Levillain, Florence, Poincloux, Renaud, Poquet, Yannick, Brandli, Irène, Wang, Chuan, Tailleux, Ludovic, Tilleul, Sylvain, Charrière, Guillaume M., Waddell, Simon J., Foti, Maria, Lugo-Villarino, Geanncarlo, Gao, Qian, Maridonneau-Parini, Isabelle, Butcher, Philip D., Castagnoli, Paola Ricciardi, Gicquel, Brigitte, de Chastellier, Chantal, Neyrolles, Olivier
Format: Article
Language:English
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Summary:Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P 1 -type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race. ► Zinc accumulates in the M. tuberculosis ( Mtb ) phagosome in macrophages (Mϕ) ► Mtb P 1 -type ATPases, including CtpC, are induced upon exposure to zinc inside Mϕ ► CtpC enables Mtb resistance to zinc poisoning and intracellular survival in Mϕ ► P 1 -type zinc efflux ATPase ZntA null E. coli is highly susceptible to Mϕ killing
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2011.08.006