The Cell Wall Lipid PDIM Contributes to Phagosomal Escape and Host Cell Exit of Mycobacterium tuberculosis
Open accessAbstract
The cell wall of Mycobacterium tuberculosis is composed of unique lipids that are important for pathogenesis. Indeed, the first-ever genetic screen in M. tuberculosis identified genes involved in the biosynthesis and transport of the cell wall lipid PDIM ( p hthiocerol dim ycocerosates) as crucial for the survival of M. tuberculosis in mice. Here we show evidence for a novel molecular mechanism of the PDIM-mediated virulence in M. tuberculosis . We characterized the DNA interaction and the regulon of Rv3167c, a transcriptional repressor that is involved in virulence regulation of M. tuberculosis , and discovered that it controls the PDIM operon. A loss-of-function genetic approach showed that PDIM levels directly correlate with the capacity of M. tuberculosis to escape the phagosome and induce host cell necrosis and macroautophagy. In conclusion, our study attributes a novel role of the cell wall lipid PDIM in intracellular host cell modulation, which is important for host cell exit and dissemination of M. tuberculosis . IMPORTANCE Mycobacterium tuberculosis is a major human pathogen that has coevolved with its host for thousands of years. The complex and unique cell wall of M. tuberculosis contains the lipid PDIM ( p hthiocerol dim ycocerosates), which is crucial for virulence of the bacterium, but its function is not well understood. Here we show that PDIM expression by M. tuberculosis is negatively regulated by a novel transcriptional repressor, Rv3167c. In addition, we discovered that the escape of M. tuberculosis from its intracellular vacuole was greatly augmented by the presence of PDIM. The increased release of M. tuberculosis into the cytosol led to increased host cell necrosis. The discovery of a link between the cell wall lipid PDIM and a major pathogenesis pathway of M. tuberculosis provides important insights into the molecular mechanisms of host cell manipulation by M. tuberculosis .
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PDIM may also facilitate phagosomal rupture and induction of the infection-promoting type I interferon response.
“PDIM may also facilitate phagosomal rupture and induction of the infection-promoting type I interferon response113,114.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [114]
The Discussion (page unavailable) says PDIM contributes to phagosomal escape and may weaken the phagosomal membrane, supporting the phagosomal-rupture portion. Our copy does not report that PDIM induces a type I interferon response; a search for interferon found no passage supporting that part. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBesides ESX-1, the mycobacterial virulence lipids phthiocerol dimycocerosates also contribute to phagosomal rupture.
“However, ESX-1 is not the only factor involved in the process; it has been shown that besides ESX-1, the mycobacterial virulence lipids phthiocerol dimycocerosates also contribute to phagosomal rupture (76)(77)(78).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [77]
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- Authors
- Quigley, J., Hughitt, V. K., Velikovsky, C. A., Mariuzza, R. A., El-Sayed, N. M., & Briken, V.
- Affiliations
- University of Maryland, College Park (US)
- Institute for Bioscience and Biotechnology Research (US)
- Corresponding author
- Briken, Volker
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2017-05-03
- Volume
- 8
- Issue
- 2
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC5340868
- OpenAlex
- W2592510217
- Cited by
- 234
- References
- 49
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 24 · 2023: 24 · 2022: 26 · 2021: 24 · 2020: 34 · 2019: 20 · 2018: 24 · 2017: 9
- FWCI
- 18.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- HHS | National Institutes of Health (AI114269)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- Mycobacterium tuberculosis, cell wall lipids, phagosome escape, transcriptional repressor, virulence regulation, macroautophagy, intracellular survival
- MeSH terms
- Autophagy, Cell Line, Cell Wall, Exocytosis, Glycolipids, Humans, Macrophages, Mycobacterium tuberculosis, Operon, Phagosomes, Repressor Proteins, Transcription, Genetic, Virulence, Cell Death, Gene Deletion, Virulence Factors, Host-Pathogen Interactions
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