Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.
Hélène Botella
(1)
,
Pascale Peyron
(1)
,
Florence Levillain
(1)
,
Renaud Poincloux
(1, 2)
,
Yannick Poquet
(1)
,
Irène Brandli
(3)
,
Chuan Wang
(4, 5)
,
Ludovic Tailleux
(6)
,
Sylvain Tilleul
(6)
,
Guillaume M Charrière
(1, 7)
,
Simon J Waddell
(8)
,
Maria Foti
(9)
,
Geanncarlo Lugo-Villarino
(1)
,
Qian Gao
(5)
,
Isabelle Maridonneau-Parini
(1)
,
Philip D Butcher
(10)
,
Paola Ricciardi Castagnoli
(11)
,
Brigitte Gicquel
(6)
,
Chantal de Chastellier
(3)
,
Olivier Neyrolles
(12, 1)
1
IPBS -
Institut de pharmacologie et de biologie structurale
2 Dynamique de la membrane et du cytosquelette
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 Department of Medical Sciences
5 Key Laboratory of Medical Molecular Virology - Fudan University
6 Génétique mycobactérienne - Mycobacterial genetics
7 NPTME - Neurobiologie, plasticité tissulaire et métabolisme énergétique
8 BSMS - Brighton and Sussex Medical School
9 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
10 St George's, University of London
11 SIgN - Singapore Immunology Network
12 GBM - Génétique et biochimie des microorganismes
2 Dynamique de la membrane et du cytosquelette
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 Department of Medical Sciences
5 Key Laboratory of Medical Molecular Virology - Fudan University
6 Génétique mycobactérienne - Mycobacterial genetics
7 NPTME - Neurobiologie, plasticité tissulaire et métabolisme énergétique
8 BSMS - Brighton and Sussex Medical School
9 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
10 St George's, University of London
11 SIgN - Singapore Immunology Network
12 GBM - Génétique et biochimie des microorganismes
Pascale Peyron
- Fonction : Auteur
- PersonId : 1386170
- IdRef : 061582271
Renaud Poincloux
- Fonction : Auteur
- PersonId : 1083824
- ORCID : 0000-0003-2884-1744
- IdRef : 225730200
Yannick Poquet
- Fonction : Auteur
- PersonId : 1105745
- IdRef : 069832307
Guillaume M Charrière
- Fonction : Auteur
- PersonId : 743764
- IdHAL : guillaume-charriere
- ORCID : 0000-0002-4796-1488
- IdRef : 07846451X
Maria Foti
- Fonction : Auteur
- PersonId : 921436
Geanncarlo Lugo-Villarino
- Fonction : Auteur
- PersonId : 178174
- IdHAL : geanncarlo-lugo
- ORCID : 0000-0003-4620-8491
Isabelle Maridonneau-Parini
- Fonction : Auteur
- PersonId : 946453
- ORCID : 0000-0003-0189-0976
- IdRef : 061582565
Olivier Neyrolles
- Fonction : Auteur
- PersonId : 178826
- IdHAL : olivier-neyrolles
- ORCID : 0000-0003-0047-5885
- IdRef : 057428050
Résumé
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.