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Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC

View ORCID ProfileLouise H. Lefrançois, View ORCID ProfileVera Kalinina, View ORCID ProfileElena Cardenal-Muñoz, View ORCID ProfileNabil Hanna, View ORCID ProfileHendrik Koliwer-Brandl, View ORCID ProfileJoddy Appiah, Florence Leuba, View ORCID ProfileHubert Hilbi, View ORCID ProfileThierry Soldati, View ORCID ProfileCaroline Barisch
doi: https://doi.org/10.1101/575217
Louise H. Lefrançois
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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Vera Kalinina
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
2Institute of Cytology, Russian Academy of Sciences, Tikhoretsky ave. 4, 194064 St. Petersburg, Russia
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Elena Cardenal-Muñoz
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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Nabil Hanna
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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Hendrik Koliwer-Brandl
3Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, 8006 Zürich, Switzerland
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Joddy Appiah
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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Florence Leuba
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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Hubert Hilbi
3Institute of Medical Microbiology, University of Zurich, Gloriastrasse 30, 8006 Zürich, Switzerland
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Thierry Soldati
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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Caroline Barisch
1Department of Biochemistry, Faculty of Science, University of Geneva, 30 quai Ernest-Ansermet, Science II, 1211 Geneva-4, Switzerland
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ABSTRACT

Macrophages use diverse strategies to kill or restrict intracellular pathogens. Some of these strategies involve the deprivation of bacteria from (micro)nutrients such as transition metals, and the bacteria intoxication through metal accumulation. Little is known about the chemical warfare between Mycobacterium marinum, a close relative of the human pathogen M. tuberculosis, and its hosts. Here we use the professional phagocyte Dictyostelium discoideum to investigate the role of Zn2+ during M. marinum infection. We show that M. marinum infection induces 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 the ZntA detoxifying transporter there is further attenuation of M. marinum growth, possibly due to a compensatory efflux of Zn2+ into the MCV. This efflux is presumably carried out by ZntB, the main Zn2+ transporter in endosomes and phagosomes. Counterintuitively, M. marinum growth is also impaired in zntB KO cells, where MCVs accumulate less Zn2+. We also demonstrate that M. marinum senses toxic levels of Zn2+ and responds by upregulating its Zn2+ exporter CtpC, which supports bacteria survival under these restrictive conditions. Attenuation of M. marinum intracellular proliferation in zntA and zntB KO cells is accentuated in the absence of CtpC, confirming that mycobacteria face noxious levels of Zn2+. Altogether, we show for the first time that M. marinum infection induces a deleterious Zn2+ elevation in D. discoideum, which is counteracted by the bacteria with the induction of its Zn2+ exporter CtpC.

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Posted March 15, 2019.
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Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC
Louise H. Lefrançois, Vera Kalinina, Elena Cardenal-Muñoz, Nabil Hanna, Hendrik Koliwer-Brandl, Joddy Appiah, Florence Leuba, Hubert Hilbi, Thierry Soldati, Caroline Barisch
bioRxiv 575217; doi: https://doi.org/10.1101/575217
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Zn2+ intoxication of Mycobacterium marinum during Dictyostelium discoideum infection is counteracted by induction of the pathogen Zn2+ exporter CtpC
Louise H. Lefrançois, Vera Kalinina, Elena Cardenal-Muñoz, Nabil Hanna, Hendrik Koliwer-Brandl, Joddy Appiah, Florence Leuba, Hubert Hilbi, Thierry Soldati, Caroline Barisch
bioRxiv 575217; doi: https://doi.org/10.1101/575217

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