Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC
| Autor: | Hanna, Nabil, Koliwer-Brandl, Hendrik, Lefrançois, Louise H, Kalinina, Vera, Cardenal-Muñoz, Elena, Appiah, Joddy, Leuba, Florence, Gueho, Aurélie, Hilbi, Hubert, Soldati, Thierry, Barisch, Caroline |
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| Přispěvatelé: | University of Zurich, Soldati, Thierry, Barisch, Caroline |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
ZnTs
animal structures Phagocyte 610 Medicine & health Vacuole M. marinum Microbiology zinc transporters Dictyostelium discoideum Host-Microbe Biology Zinc transporters medicine Dictyostelium Mycobacterium marinum Phagosome CtpC zinc poisoning biology 10179 Institute of Medical Microbiology Chemistry Intracellular parasite Poisoning 2404 Microbiology biochemical phenomena metabolism and nutrition bacterial infections and mycoses biology.organism_classification infection QR1-502 Zinc medicine.anatomical_structure D. discoideum Vacuoles ddc:540 2406 Virology 570 Life sciences Efflux Carrier Proteins Infection Intracellular Research Article |
| Zdroj: | mBio, Vol. 12, No e01313 (2021) mBio, Vol 12, Iss 1 (2021) mBio |
| ISSN: | 2150-7511 |
| Popis: | Microelements are essential for the function of the innate immune system. A deficiency in zinc or copper results in an increased susceptibility to bacterial infections. Macrophages use diverse strategies to restrict intracellular pathogens, including either depriving the bacteria of (micro)nutrients such as transition metals or intoxicating them via metal accumulation. Little is known about the chemical warfare between Mycobacterium marinum, a close relative of Mycobacterium tuberculosis (Mtb), and its hosts. We use the professional phagocyte Dictyostelium discoideum to investigate the role of Zn2+ during M. marinum infection. We show that M. marinum senses toxic levels of Zn2+ and responds by upregulating one of its isoforms of the Zn2+ efflux transporter CtpC. Deletion of ctpC (MMAR_1271) leads to growth inhibition in broth supplemented with Zn2+ as well as reduced intracellular growth. Both phenotypes were fully rescued by constitutive ectopic expression of the Mtb CtpC orthologue demonstrating that MMAR_1271 is the functional CtpC Zn2+ efflux transporter in M. marinum. Infection leads to the accumulation of Zn2+ inside the Mycobacterium-containing vacuole (MCV), achieved by the induction and recruitment of the D. discoideum Zn2+ efflux pumps ZntA and ZntB. In cells lacking ZntA, there is further attenuation of M. marinum growth, presumably due to a compensatory efflux of Zn2+ into the MCV, carried out by ZntB, the main Zn2+ transporter in endosomes and phagosomes. Counterintuitively, bacterial growth is also impaired in zntB KO cells, in which MCVs appear to accumulate less Zn2+ than in wild-type cells, suggesting restriction by other Zn2+-mediated mechanisms. Absence of CtpC further epistatically attenuates the intracellular proliferation of M. marinum in zntA and zntB KO cells, confirming that mycobacteria face noxious levels of Zn2+. |
| Databáze: | OpenAIRE |
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