Abstract
ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Mice
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Mycobacterium abscessus* / genetics
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Mycobacterium marinum* / metabolism
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Mycobacterium tuberculosis* / genetics
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Mycobacterium* / genetics
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Type VII Secretion Systems* / genetics
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Type VII Secretion Systems* / metabolism
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Zebrafish / metabolism
Substances
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Bacterial Proteins
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Type VII Secretion Systems
Grants and funding
This project received funding from the European Union’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie grant agreement no 846476 (to C.P.) and from the Joachim Herz Stiftung, Hamburg, Germany (to M.W. and F.P.M. as members of the Infectophysics Consortium). F.P.M. was supported by a financial grant from Mukoviszidose Institut gGmbH, Bonn, the research and development arm of the German Cystic Fibrosis Association Mukoviszidose e.V. M.L. received funding from the French associations ‘Vaincre la mucoviscidose Association and Grégory Lemarchal Association’ (grant agreement n°RIF20190502522). MDJ received a post-doctoral fellowship from the Labex EpiGenMed, program «Investissements d’avenir» (ANR-10-LABX-12-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.