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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Panas, MW; Sixsmith, JD; White, K; Korioth-Schmitz, B; Shields, ST; Moy, BT; Lee, S; Schmitz, JE; Jacobs, WR; Porcelli, SA; Haynes, BF; Letvin, NL; Gillard, GO

Published Date

  • December 2014

Published In

Volume / Issue

  • 82 / 12

Start / End Page

  • 5317 - 5326

PubMed ID

  • 25287928

Pubmed Central ID

  • 25287928

Electronic International Standard Serial Number (EISSN)

  • 1098-5522

International Standard Serial Number (ISSN)

  • 0019-9567

Digital Object Identifier (DOI)

  • 10.1128/IAI.02100-14

Language

  • eng