title: Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.
abstract: 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.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Botella
authors.forename: Pascale
authors.initials: P
authors.lastname: Peyron
authors.forename: Florence
authors.initials: F
authors.lastname: Levillain
authors.forename: Renaud
authors.initials: R
authors.lastname: Poincloux
authors.forename: Yannick
authors.initials: Y
authors.lastname: Poquet
authors.forename: Irène
authors.initials: I
authors.lastname: Brandli
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.forename: Ludovic
authors.initials: L
authors.lastname: Tailleux
authors.forename: Sylvain
authors.initials: S
authors.lastname: Tilleul
authors.forename: Guillaume M
authors.initials: GM
authors.lastname: Charrière
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Waddell
authors.forename: Maria
authors.initials: M
authors.lastname: Foti
authors.forename: Geanncarlo
authors.initials: G
authors.lastname: Lugo-Villarino
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maridonneau-Parini
authors.forename: Philip D
authors.initials: PD
authors.lastname: Butcher
authors.forename: Paola Ricciardi
authors.initials: PR
authors.lastname: Castagnoli
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gicquel
authors.forename: Chantal
authors.initials: C
authors.lastname: de Chastellier
authors.forename: Olivier
authors.initials: O
authors.lastname: Neyrolles
mesh_terms: D000818:Animals; D025243:Bacterial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000378:metabolism* / Q000382:microbiology; D015032:Zinc / Q000378:metabolism* / Q000633:toxicity
chemical_list: D025243:Bacterial Proton-Translocating ATPases; D015032:Zinc