Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling

Dong Min Shin, Bo Young Jeon, Hye Mi Lee, Hyo Sun Jin, Jae Min Yuk, Chang Hwa Song, Sang Hee Lee, Zee Won Lee, Sang Nae Cho, Jin Man Kim, Richard L. Friedman, Eun Kyeong Jo

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179 Scopus citations

Abstract

The "enhanced intracellular survival" (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage autophagy, inflammatory responses, and cell death via a reactive oxygen species (ROS)- dependent pathway. Macrophages infected with an Mtb eis-deletion mutant H37Rv (Mtb-Deis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Deis increased the production of tumor necrosis factor-a and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Deis (for which NADPH oxidase and mitochondria were largely responsible) rendered the cells highly sensitive to autophagy activation and cytokine production. Despite considerable activation of autophagy and proinflammatory responses, macrophages infected with Mtb-Deis underwent caspase-independent cell death. This cell death was significantly inhibited by blockade of autophagy and c-Jun N-terminal kinase-ROS signaling, suggesting that excessive autophagy and oxidative stress are detrimental to cell survival. Finally, artificial over-expression of Eis or pretreatment with recombinant Eis abrogated production of both ROS and proinflammatory cytokines, which depends on the N-acetyltransferase domain of the Eis protein. Collectively, these data indicate that Mtb Eis suppresses host innate immune defenses by modulating autophagy, inflammation, and cell death in a redox-dependent manner.

Original languageEnglish (US)
Article numbere1001230
JournalPLoS pathogens
Volume6
Issue number12
DOIs
StatePublished - Dec 1 2010

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Shin, D. M., Jeon, B. Y., Lee, H. M., Jin, H. S., Yuk, J. M., Song, C. H., Lee, S. H., Lee, Z. W., Cho, S. N., Kim, J. M., Friedman, R. L., & Jo, E. K. (2010). Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. PLoS pathogens, 6(12), [e1001230]. https://doi.org/10.1371/journal.ppat.1001230