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

Hsu, T, Hingley-Wilson, Suzie, Chen, B, Chen, M, Dai, AZ, Morin, PM, Marks, CB, Padiyar, J, Goulding, C, Gingery, M , Eisenberg, D, Russell, RG, Derrick, SC, Collins, FM, Morris, SL, King, CH and Jacobs, WR Jr (2003) The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue Proceedings of the National Academy of Sciences of the United States of America, 100 (21). pp. 12420-12425.

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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 ΔRD1 mutants were significantly attenuated for virulence in both immunocompromised and immunocompetent mice. The M. tuberculosis ΔRD1 mutants were also shown to protect mice against aerosol challenge, in a similar manner to BCG. Interestingly, the ΔRD1 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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Hsu, TUNSPECIFIEDUNSPECIFIED
Hingley-Wilson, Suzies.hingley-wilson@surrey.ac.ukUNSPECIFIED
Chen, BUNSPECIFIEDUNSPECIFIED
Chen, MUNSPECIFIEDUNSPECIFIED
Dai, AZUNSPECIFIEDUNSPECIFIED
Morin, PMUNSPECIFIEDUNSPECIFIED
Marks, CBUNSPECIFIEDUNSPECIFIED
Padiyar, JUNSPECIFIEDUNSPECIFIED
Goulding, CUNSPECIFIEDUNSPECIFIED
Gingery, MUNSPECIFIEDUNSPECIFIED
Eisenberg, DUNSPECIFIEDUNSPECIFIED
Russell, RGUNSPECIFIEDUNSPECIFIED
Derrick, SCUNSPECIFIEDUNSPECIFIED
Collins, FMUNSPECIFIEDUNSPECIFIED
Morris, SLUNSPECIFIEDUNSPECIFIED
King, CHUNSPECIFIEDUNSPECIFIED
Jacobs, WR JrUNSPECIFIEDUNSPECIFIED
Date : 14 October 2003
Identification Number : 10.1073/pnas.1635213100
Copyright Disclaimer : Copyright © 2003, The National Academy of Sciences of the USA
Depositing User : Jane Hindle
Date Deposited : 26 Oct 2017 12:54
Last Modified : 26 Oct 2017 12:54
URI: http://epubs.surrey.ac.uk/id/eprint/844665

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