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Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence
Open accessAbstract
A key to the pathogenic success of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the capacity to survive within host macrophages. Although several factors required for this survival have been identified, a comprehensive knowledge of such factors and how they work together to manipulate the host environment to benefit bacterial survival are not well understood. To systematically identify Mtb factors required for intracellular growth, we screened an arrayed, non-redundant Mtb transposon mutant library by high-content imaging to characterize the mutant-macrophage interaction. Based on a combination of imaging features, we identified mutants impaired for intracellular survival. We then characterized the phenotype of infection with each mutant by profiling the induced macrophage cytokine response. Taking a systems-level approach to understanding the biology of identified mutants, we performed a multiparametric analysis combining pathogen and host phenotypes to predict functional relationships between mutants based on clustering. Strikingly, mutants defective in two well-known virulence factors, the ESX-1 protein secretion system and the virulence lipid phthiocerol dimycocerosate (PDIM), clustered together. Building upon the shared phenotype of loss of the macrophage type I interferon (IFN) response to infection, we found that PDIM production and export are required for coordinated secretion of ESX-1-substrates, for phagosomal permeabilization, and for downstream induction of the type I IFN response. Multiparametric clustering also identified two novel genes that are required for PDIM production and induction of the type I IFN response. Thus, multiparametric analysis combining host and pathogen infection phenotypes can be used to identify novel functional relationships between genes that play a role in infection.
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“The DosR system activates transcription of hrp1, a PDIM synthesis factor113, during short-term and long-term oxygen deprivation57,115.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [113]
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“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 [113]
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“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 [78]
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Metadata
- Authors
- Barczak, A. K., Avraham, R., Singh, S., Luo, S. S., Zhang, W. R., Bray, M.-A., Hinman, A. E., Thompson, M., Nietupski, R. M., Golas, A., Montgomery, P., Fitzgerald, M., Smith, R. S., White, D. W., Tischler, A. D., Carpenter, A. E., & Hung, D. T.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- University of Minnesota (US)
- Corresponding author
- Hung, Deborah T.
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-05-15
- Volume
- 13
- Issue
- 5
- Pages
- e1006363
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC5444860
- OpenAlex
- W2615762114
- Cited by
- 120
- References
- 62
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 11 · 2023: 14 · 2022: 12 · 2021: 10 · 2020: 14 · 2019: 13 · 2018: 12 · 2017: 4
- FWCI
- 9.05
- Type
- journal article
- Language
- en
- Update notices
- new_version (2017-05-25)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (K08-AI080944)
- Massachusetts General Hospital (Claflin Award)
- Ragon Institute (TB Seed Grant)
- Broad Institute Tuberculosis Donor Group and Pershing Square Foundation
- Harvard University Center for AIDS Research (US) (P30-AI060354)
- Massachusetts General Hospital Department of Medicine (Pingree Transformative Scholar Award)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
- Keywords
- Mycobacterium tuberculosis, intracellular survival, macrophages, virulence factors, ESX-1 secretion system, phthiocerol dimycocerosate, type I interferon response, transposon mutant library, high-content imaging, macrophage cytokine response, tuberculosis pathogenesis
- MeSH terms
- Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Macrophages, Mutation, Mycobacterium tuberculosis, Phagosomes, Phenotype, Tuberculosis, Virulence, Gene Library, Cytokines, Mice, Host-Pathogen Interactions
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