A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis

Kari A. Sweeney, Dee N. Dao, Michael F. Goldberg, Tsungda Hsu, Manjunatha M. Venkataswamy, Marcela Henao-Tamayo, Diane Ordway, Rani S. Sellers, Paras Jain, Bing Chen, Mei Chen, John Kim, Regy Lukose, John Chan, Ian M. Orme, Steven A. Porcelli, William R. Jacobs

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly lethal, infection with an M. smegmatis Î "esx-3 mutant (here designated as the IKE strain) was controlled and cleared by a MyD88-dependent bactericidal immune response. Introduction of the orthologous Mycobacterium tuberculosis esx-3 genes into the IKE strain resulted in a strain, designated IKEPLUS, that remained susceptible to innate immune killing and was highly attenuated in mice but had a marked ability to stimulate bactericidal immunity against challenge with virulent M. tuberculosis. Analysis of these adaptive immune responses indicated that the highly protective bactericidal immunity elicited by IKEPLUS was dependent on CD4 + memory T cells and involved a distinct shift in the pattern of cytokine responses by CD4 + cells. Our results establish a role for the esx-3 locus in promoting mycobacterial virulence and also identify the IKE strain as a potentially powerful candidate vaccine vector for eliciting protective immunity to M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)1261-1268
Number of pages8
JournalNature Medicine
Volume17
Issue number10
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sweeney, K. A., Dao, D. N., Goldberg, M. F., Hsu, T., Venkataswamy, M. M., Henao-Tamayo, M., Ordway, D., Sellers, R. S., Jain, P., Chen, B., Chen, M., Kim, J., Lukose, R., Chan, J., Orme, I. M., Porcelli, S. A., & Jacobs, W. R. (2011). A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nature Medicine, 17(10), 1261-1268. https://doi.org/10.1038/nm.2420