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

Authors
 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 
Citation
 PLOS PATHOGENS, Vol.6(12) : e1001230, 2010 
Journal Title
 PLOS PATHOGENS 
ISSN
 1553-7366 
Issue Date
2010
MeSH
Acetyltransferases ; Animals ; Antigens, Bacterial/physiology* ; Autophagy* ; Bacterial Proteins/physiology* ; Cell Death ; Host-Pathogen Interactions/immunology* ; Immunity, Innate ; Inflammation* ; Macrophages/metabolism ; Macrophages/microbiology ; Mice ; Mycobacterium tuberculosis/chemistry ; Mycobacterium tuberculosis/physiology* ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology*
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-Δeis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Δeis increased the production of tumor necrosis factor-α and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Δeis (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-Δeis 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
Files in This Item:
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DOI
10.1371/journal.ppat.1001230
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Cho, Sang Nae(조상래)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103277
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