Disruption of the ESX‐5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation
Open accessAbstract
Summary: The chromosome of Mycobacterium tuberculosis encodes five type VII secretion systems (ESX‐1–ESX‐5). While the role of the ESX‐1 and ESX‐3 systems in M. tuberculosis has been elucidated, predictions for the function of the ESX‐5 system came from data obtained in Mycobacterium marinum , where it transports PPE and PE_PGRS proteins and modulates innate immune responses. To define the role of the ESX‐5 system in M. tuberculosis , in this study, we have constructed five M. tuberculosis H37Rv ESX‐5 knockout/deletion mutants, inactivating eccA 5 , eccD 5 , rv1794 and esxM genes or the ppe25‐pe19 region. Whereas the Mtb rv1794 ko displayed no obvious phenotype, the other four mutants showed defects in secretion of the ESX‐5‐encoded EsxN and PPE41, a representative member of the large PPE protein family. Strikingly, the Mtb eccD 5 ko mutant also showed enhanced sensitivity to detergents and hydrophilic antibiotics. When the virulence of the five mutants was evaluated, the Mtb eccD 5 ko and MtbΔ ppe25‐pe19 mutants were found attenuated both in macrophages and in the severe combined immune‐deficient mouse infection model. Altogether these findings indicate an essential role of ESX‐5 for transport of PPE proteins, cell wall integrity and full virulence of M. tuberculosis , thereby opening interesting new perspectives for the study of this human pathogen.
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- Authors
- Bottai, D., Di Luca, M., Majlessi, L., Frigui, W., Simeone, R., Sayes, F., Bitter, W., Brennan, M. J., Leclerc, C., Batoni, G., Campa, M., Brosch, R., & Esin, S.
- Affiliations
- University of Pisa (IT)
- Inserm (FR)
- Institut Pasteur (FR)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Aeras (US)
- Corresponding author
- Bottai, Daria
- ORCID
- Venue
- Molecular Microbiology
- Publisher
- Wiley
- Published
- 2012-02-20
- Volume
- 83
- Issue
- 6
- Pages
- 1195-1209
- ISSN
- 0950-382X (ISSN-L)
- 1365-2958
- OpenAlex
- W2135524542
- Cited by
- 210
- References
- 54
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 7 · 2023: 15 · 2022: 9 · 2021: 12 · 2020: 17 · 2019: 17 · 2018: 18 · 2017: 13 · 2016: 21 · 2015: 15 · 2014: 13 · 2013: 14 · 2012: 11
- FWCI
- 11.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion)
- HAL (submittedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Damascus University
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Keywords
- Mycobacterium tuberculosis, type VII secretion system, PPE proteins, cell wall integrity, virulence attenuation, macrophage infection, SCID mouse model, detergent sensitivity, antibiotic susceptibility, knockout mutants
- MeSH terms
- Animals, Bacterial Proteins, Cell Wall, Cells, Cultured, Humans, Macrophages, Mycobacterium tuberculosis, Tuberculosis, Virulence, Mice, SCID, Amino Acid Motifs, Protein Transport, Mice, Bacterial Secretion Systems
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