{
  "abstract": "During infection, pathogenic mycobacteria damage the membrane of the Mycobacterium-containing vacuole (MCV), triggering host repair responses that preserve an intracellular permissive niche before bacteria escape to the cytosol at later stages. How the MCV transitions from repairable injury to catastrophic rupture remains poorly understood. Here, we dissected the respective contributions of the ESX-1 effectors EsxA/EsxB and the cell-envelope lipid phthiocerol dimycocerosate (PDIM) during Mycobacterium marinum infection of the amoeba Dictyostelium discoideum. Combining host reporters for membrane damage and repair with single and double bacteria mutants, we show that EsxA/EsxB and PDIM are both required for full intracellular virulence but act at distinct stages of MCV damage progression. Loss of EsxA/EsxB strongly reduced recruitment of ESCRT and autophagy reporters to the MCV, demonstrating that EsxA initiates repairable membrane lesions. In contrast, PDIM-deficient bacteria retained the ability to recruit early damage reporters and ESCRT machinery but showed reduced autophagy-associated repair, failed to efficiently acquire cytosolic perilipin coating, and remained largely confined within the MCV. Genetic disruption of host autophagy restored cytosolic access and increased intracellular growth of PDIM-deficient bacteria, indicating that PDIM is specifically required to overcome host repair capacity rather than to initiate damage. Importantly, the sequential requirement for EsxA and PDIM was conserved during infection of murine microglial BV-2 cells. Remarkably, PDIM-defective mutant induced lysenin recruitment, a reporter of sphingomyelin exposure, but progression to autophagy engagement was strongly decreased. Together, our results support a two-step model in which EsxA initiates MCV membrane damage, while PDIM amplifies these lesions towards catastrophic rupture, enabling escape to the cytosol and dissemination. Author summary: Pathogenic mycobacteria, including the agent of tuberculosis, infect host cells and reside in a membrane-delimited compartment. During infection, the membrane of this compartment is damaged, activating host repair mechanisms that initially contain the injury and maintain the bacteria inside the compartment. At later stages, the bacteria escape into the host cell cytosol, allowing the progression of the infection, but how this transition from repairable damage to full membrane rupture occurs is not well understood. Using Mycobacterium marinum infection of amoebae and mammalian cells, we found that two previously characterized bacterial factors act in sequence. EsxA, a secreted bacterial protein, triggers initial membrane damage that can be controlled by host repair systems. In contrast, PDIM, a lipid present at the bacterial surface, allows bacteria to overcome these repair mechanisms and progress toward irreversible membrane disruption. Together, our results show how pathogenic mycobacteria use a two-step process to first induce repairable membrane damage and then bypass host repair systems, enabling escape to the cytosol and successful infection.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry, Faculty of Science, University of Geneva, Geneva, Switzerland",
    "Institute of Medical Microbiology, Faculty of Medicine, University of Zurich, Zurich, Switzerland"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Céline Michard",
      "orcid": "0000-0001-5215-8510"
    },
    {
      "affs": [
        0
      ],
      "name": "Angélique Perret",
      "orcid": "0000-0001-8445-6424"
    },
    {
      "affs": [
        0
      ],
      "name": "Mélanie Foulon"
    },
    {
      "affs": [
        1
      ],
      "name": "Hendrik Koliwer-Brandl"
    },
    {
      "affs": [
        1
      ],
      "name": "Hubert Hilbi",
      "orcid": "0000-0002-5462-9301"
    },
    {
      "affs": [
        0
      ],
      "name": "Thierry Soldati",
      "orcid": "0000-0002-2056-7931"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4xww6qjnmxgms.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014721",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014721",
  "id": "4xww6qjnmxgms",
  "issns": [
    "1553-7374",
    "1553-7366"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014721",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Actinobacteria"
    ],
    [
      "heading",
      "Autophagic Cell Death"
    ],
    [
      "heading",
      "Bacteria"
    ],
    [
      "heading",
      "Bacterial Pathogens"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "heading",
      "Cell Death"
    ],
    [
      "heading",
      "Cell Membranes"
    ],
    [
      "heading",
      "Cell Processes"
    ],
    [
      "heading",
      "Cellular Structures and Organelles"
    ],
    [
      "heading",
      "Cytosol"
    ],
    [
      "heading",
      "Echinococcosis"
    ],
    [
      "heading",
      "Helminth Infections"
    ],
    [
      "heading",
      "Intracellular Membranes"
    ],
    [
      "heading",
      "Intracellular Pathogens"
    ],
    [
      "heading",
      "Medical Conditions"
    ],
    [
      "heading",
      "Medical Microbiology"
    ],
    [
      "heading",
      "Medicine and Health Sciences"
    ],
    [
      "heading",
      "Microbial Pathogens"
    ],
    [
      "heading",
      "Microbiology"
    ],
    [
      "heading",
      "Mycobacteria"
    ],
    [
      "heading",
      "Mycobacterium Tuberculosis"
    ],
    [
      "heading",
      "Neglected Tropical Diseases"
    ],
    [
      "heading",
      "Organisms"
    ],
    [
      "heading",
      "Parasitic Diseases"
    ],
    [
      "heading",
      "Pathogens"
    ],
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      "heading",
      "Pathology and Laboratory Medicine"
    ],
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      "heading",
      "Physiological Processes"
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    [
      "heading",
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      "heading",
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    ],
    [
      "heading",
      "Secretion"
    ],
    [
      "heading",
      "Tropical Diseases"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Autophagic cell death"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cell membranes/Intracellular membranes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cytosol"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Bacterial pathogens/Mycobacteria"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Actinobacteria/Mycobacteria"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Actinobacteria/Mycobacterium tuberculosis"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Physiological processes/Secretion"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages"
    ],
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      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Intracellular pathogens"
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  "openalex": "W7223093746",
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014721&type=printable",
  "pmcid": "PMC13712727",
  "pmid": "42905778",
  "published": "2026-10-21",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/4xww6qjnmxgms.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:23Z",
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      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014721"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "heading:Microbiology",
      "subfield": "microbiology"
    },
    {
      "field": "medicine",
      "origin": "heading:Physiology",
      "subfield": "physiology"
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  ],
  "title": "PDIM drives the transition from repairable to catastrophic EsxA-mediated vacuole membrane damage during Mycobacterium marinum infection",
  "title_text": "PDIM drives the transition from repairable to catastrophic EsxA-mediated vacuole membrane damage during Mycobacterium marinum infection",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:15Z",
  "url": "https://research.draconitic.com/paper/4xww6qjnmxgms",
  "venue": "PLOS Pathogens",
  "versions": []
}