Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses

Michael W. Panas, Jaimie D. Sixsmith, Keri Ann White, Birgit Korioth-Schmitz, Shana T. Shields, Brian T. Moy, Sunhee Lee, Joern E. Schmitz, William R. Jacobs, Steven A. Porcelli, Barton F. Haynes, Norman L. Letvin, Geoffrey O. Gillard

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8+ T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium- encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product-specific CD8+ T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8+ T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8+ T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors.

Original languageEnglish (US)
Pages (from-to)5317-5326
Number of pages10
JournalInfection and immunity
Volume82
Issue number12
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Panas, M. W., Sixsmith, J. D., White, K. A., Korioth-Schmitz, B., Shields, S. T., Moy, B. T., Lee, S., Schmitz, J. E., Jacobs, W. R., Porcelli, S. A., Haynes, B. F., Letvin, N. L., & Gillard, G. O. (2014). Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses. Infection and immunity, 82(12), 5317-5326. https://doi.org/10.1128/IAI.02100-14