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.
Highlights
Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that can survive and even multiply within host macrophages [1,2]
Autophagy has emerged as a host defense strategy against Mtb infection, through stimulation of the fusion of phagosomes and lysosomes
Excessive and uncontrolled autophagic activity can be detrimental to host cells and can result in their death
Summary
Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that can survive and even multiply within host macrophages [1,2]. The removal of aged organelles, plays a central role in regulating important cellular functions [5,6] and aids in innate and adaptive immune defense against Mtb and other intracellular pathogens [5,7,8,9]. Physiological or pharmacological induction of autophagy in macrophages results in increased colocalization of mycobacterial phagosomes and the autophagy effector LC3, and the fusion of the former with lysosomes, which overcomes the blockade of membrane trafficking and increased bactericidal activity [7]. Autophagy plays key roles in host innate and adaptive immune defenses, it can, under certain circumstances, result in type II programmed cell death [10,11]. The genetic basis for mycobacterial induction of autophagy, and its implications for host cell viability, remain to be elucidated
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