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Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages

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posted on 2023-06-07, 16:23 authored by Hélène Botella, Pascale Peyron, Florence Levillain, Renaud Poincloux, Yannick Poquet, Irène Brandli, Chuan Wang, Ludovic Tailleux, Sylvain Tilleul, Guillaume M Charrière, Simon WaddellSimon Waddell, Maria Foti, Geanncarlo Lugo-Villarino, Qian Gao, Isabelle Maridonneau-Parini, Philip D Butcher, Paola Ricciardi Castagnoli, Brigitte Gicquel, Chantal de Chastellier, Olivier Neyrolles
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.

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Publication status

  • Published

File Version

  • Published version

Journal

Cell Host and Microbe

ISSN

1931-3128

Publisher

Elsevier

Issue

3

Volume

10

Page range

248-259

Department affiliated with

  • Global Health and Infection Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2012-07-17

First Open Access (FOA) Date

2017-01-10

First Compliant Deposit (FCD) Date

2017-01-10

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