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A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis

Nature Medicine volume 8, pages 1171–1174 (2002)Cite this article

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Abstract

With the advent of HIV and the widespread emergence of drug-resistant strains of Mycobacterium tuberculosis, newer control strategies in the form of a better vaccine could decrease the global incidence of tuberculosis. A desirable trait in an effective live attenuated vaccine strain is an ability to persist within the host in a limited fashion in order to produce important protective antigens in vivo1,2. Attenuated M. tuberculosis vaccine candidates have been constructed by deleting genes required for growth in mice3,4,5. These candidate vaccines did not elicit adequate protective immunity in animal models, due to their inability to persist sufficiently long within the host tissues. Here we report that an auxotrophic mutant of M. tuberculosis defective in the de novo biosynthesis of pantothenic acid (vitamin B5) is highly attenuated in immunocompromised SCID mice and in immunocompetent BALB/c mice. SCID mice infected with the pantothenate auxotroph survived significantly longer (250 days) than mice infected with either bacille Calmette-Guerin (BCG) vaccine or virulent M. tuberculosis (77 and 35 days, respectively). Subcutaneous immunization with this auxotroph conferred protection in C57BL/6J mice against an aerosol challenge with virulent M. tuberculosis, which was comparable with that afforded by BCG vaccination. Our findings highlight the importance of de novo pantothenate biosynthesis in limiting the intracellular survival and pathogenesis of M. tuberculosis without reducing its immunogenicity in vaccinated mice.

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Figure 1: Pathway for the biosynthesis of pantothenic acid and coenzyme A and its disruption in M. tuberculosis.
Figure 2: Pantothenate auxotrophy leads to attenuation of ΔpanCD mutant in mice.
Figure 3: The ΔpanCD mutant produces less tissue pathology in lungs of infected BALB/c mice.

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  • 23 September 2002

    This was incorrect in AOP version but corrected in print. Transposed panels b and care now corrected in this updated figure.

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Acknowledgements

We thank J. Chan, S. Bardarov for helpful comments and J. Kriakov for providing the phage phAE159. Correspondence and requests for materials should be addressed to W.R.J.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA

    Vasan K. Sambandamurthy, Bing Chen & William R. Jacobs Jr

  2. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA

    Vasan K. Sambandamurthy, Xiaojuan Wang, Bing Chen & William R. Jacobs Jr

  3. Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA

    Robert G. Russell

  4. Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA

    Steven Derrick, Frank M. Collins & Sheldon L. Morris

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  1. Vasan K. Sambandamurthy
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Correspondence to William R. Jacobs Jr.

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Sambandamurthy, V., Wang, X., Chen, B. et al. A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nat Med 8, 1171–1174 (2002). https://doi.org/10.1038/nm765

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