Cited by 731Tuberculosis Research and EpidemiologyImmune responses and vaccinationsInfectious Diseases and Tuberculosis

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The primary mechanism of attenuation of bacillus Calmette–Guérin is a loss of secreted lytic function required for invasion of lung interstitial tissue

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Hsu, Tsungda, Hingley-Wilson, Suzanne M., Chen, Bing, Chen, Mei, Dai, Annie Z., Morin, Paul M., Marks, Carolyn B., Padiyar, Jeevan, Goulding, Celia, Gingery, Mari, Eisenberg, David, Russell, Robert G., Derrick, Steven C., Collins, Frank M., Morris, Sheldon L., King, C. Harold, Jacobs, William R.·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1635213100PMC PMC218773

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Abstract

Tuberculosis remains a leading cause of death worldwide, despite the availability of effective chemotherapy and a vaccine. Bacillus Calmette–Guérin (BCG), the tuberculosis vaccine, is an attenuated mutant of Mycobacterium bovis that was isolated after serial subcultures, yet the functional basis for this attenuation has never been elucidated. A single region ( RD1 ), which is absent in all BCG substrains, was deleted from virulent M. bovis and Mycobacterium tuberculosis strains, and the resulting Δ RD1 mutants were significantly attenuated for virulence in both immunocompromised and immunocompetent mice. The M. tuberculosis Δ RD1 mutants were also shown to protect mice against aerosol challenge, in a similar manner to BCG. Interestingly, the Δ RD1 mutants failed to cause cytolysis of pneumocytes, a phenotype that had been previously used to distinguish virulent M. tuberculosis from BCG. A specific transposon mutation, which disrupts the Rv3874 Rv3875 ( cfp-10 esat-6 ) operon of RD1 , also caused loss of the cytolytic phenotype in both pneumocytes and macrophages. This mutation resulted in the attenuation of virulence in mice, as the result of reduced tissue invasiveness. Moreover, specific deletion of each transcriptional unit of RD1 revealed that three independent transcriptional units are required for virulence, two of which are involved in the secretion of ESAT-6 (6-kDa early secretory antigenic target). We conclude that the primary attenuating mechanism of bacillus Calmette–Guérin is the loss of cytolytic activity mediated by secreted ESAT-6, which results in reduced tissue invasiveness.

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Authors: Hsu, T., Hingley-Wilson, S. M., Chen, B., Chen, M., Dai, A. Z., Morin, P. M., Marks, C. B., Padiyar, J., Goulding, C., Gingery, M., Eisenberg, D., Russell, R. G., Derrick, S. C., Collins, F. M., Morris, S. L., King, C. H., & Jacobs, W. R.
Affiliations: Albert Einstein College of Medicine (US)
Howard Hughes Medical Institute, Departments of Pathology and Microbiology and Immunology, and Analytic Imaging Facility, Albert Einstein College of Medicine, Bronx, NY 10461; UCLA–DOE Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095-1570; Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892; and Division of Infectious Diseases, Department of Medicine, Emory School of Medicine, Atlanta, GA 30303
ORCID: Chen, Bing
Chen, Mei
Goulding, Celia
Eisenberg, David
Derrick, Steven C.
Jacobs, William R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-10-13
Volume: 100
Issue: 21
Pages: 12420-12425
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1635213100
PMC: PMC218773
OpenAlex: W2036635548
Cited by: 731
References: 28
Citations by year: 2026: 18 · 2025: 31 · 2024: 21 · 2023: 24 · 2022: 27 · 2021: 25 · 2020: 33 · 2019: 39 · 2018: 25 · 2017: 31 · 2016: 41 · 2015: 42 · 2014: 46 · 2013: 36 · 2012: 37
FWCI: 16.70
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Open Research (University of Surrey) (submittedVersion)
Funders: National Institutes of Health (1r21ai052356-01)
National Institute of General Medical Sciences (GM 62410, P50GM062410)
National Institute of Allergy and Infectious Diseases (R01AI026170, AI-26170, AI 52356, R37AI026170)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
Keywords: BCG, Mycobacterium bovis, Mycobacterium tuberculosis, virulence attenuation, ESAT-6, CFP-10, aerosol challenge, transposon mutagenesis, tuberculosis vaccine
MeSH terms: Animals, Antigens, Bacterial, Bacterial Proteins, BCG Vaccine, Cell Line, Genes, Bacterial, Genetic Complementation Test, Humans, Lung, Mice, Inbred BALB C, Mice, Inbred C57BL, Mycobacterium bovis, Mycobacterium tuberculosis, Operon, Virulence, Mice, SCID, Gene Deletion, Mice

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The primary mechanism of attenuation of bacillus Calmette–Guérin is a loss of secreted lytic function required for invasion of lung interstitial tissue

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