Mycobacterium tuberculosis Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling

PLoS Pathogens

Hye-Mi Lee¹  Jin-Man Kim²  Chang-Hwa Song²  Dong-Min Shin²  Zee-Won Lee²  Hyo Sun Jin²  Eun-Kyeong Jo³  Sang-Nae Cho⁴  Bo-Young Jeon⁴  Sang-Hee Lee⁴  Jae-Min Yuk⁴  Richard L. Friedman⁴ 

[1] Department of Microbiology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea;Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Korea;Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea;Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, Korea

关键词: Autophagic cell death;    Macrophages;    Mycobacterium tuberculosis;    Cytokines;    Apoptosis;    Inflammation;    Cell staining;    Vacuoles;   

DOI  :  10.1371/journal.ppat.1001230

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY