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

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          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.

          Author Summary

          Tuberculosis is a global health problem: at least one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb). Mtb is a successful pathogen that enhances its own intracellular survival by arresting phagolysosomal fusion. Recently, autophagy has emerged as a host defense strategy against Mtb infection, through stimulation of the fusion of phagosomes and lysosomes. However, excessive and uncontrolled autophagic activity can be detrimental to host cells and can result in their death. The Mtb “enhanced intracellular survival” ( eis) gene has been implicated in the intracellular survival of M. smegmatis. However, its exact role and how it regulates host innate immune responses have not been fully explained. Here, we provide evidence that Eis suppresses macrophage autophagy, inflammation, and cell death through the inhibition of reactive oxygen species (ROS) generation. Although it has previously been demonstrated that autophagy is a key host defense response to mycobacterial infections, our data indicate that excessive autophagy, and the resulting cell death, do not significantly affect host defense responses to mycobacteria. Additionally, our data reveal that Eis's ability to regulate ROS generation and proinflammatory responses depends on its N-acetyltransferase domain. These results underscore a previously unrecognized role of Eis in modulating host inflammatory responses, oxidative stress, and cell survival/death during mycobacterial infection.

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          Most cited references 47

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          Life and death partners: apoptosis, autophagy and the cross-talk between them.

          It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the cross-talk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment.
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            Dissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem Cells

            In macroautophagy, cytoplasmic components are delivered to lysosomes for degradation via autophagosomes that are formed by closure of cup-shaped isolation membranes. However, how the isolation membranes are formed is poorly understood. We recently found in yeast that a novel ubiquitin-like system, the Apg12-Apg5 conjugation system, is essential for autophagy. Here we show that mouse Apg12-Apg5 conjugate localizes to the isolation membranes in mouse embryonic stem cells. Using green fluorescent protein–tagged Apg5, we revealed that the cup-shaped isolation membrane is developed from a small crescent-shaped compartment. Apg5 localizes on the isolation membrane throughout its elongation process. To examine the role of Apg5, we generated Apg5-deficient embryonic stem cells, which showed defects in autophagosome formation. The covalent modification of Apg5 with Apg12 is not required for its membrane targeting, but is essential for involvement of Apg5 in elongation of the isolation membranes. We also show that Apg12-Apg5 is required for targeting of a mammalian Aut7/Apg8 homologue, LC3, to the isolation membranes. These results suggest that the Apg12-Apg5 conjugate plays essential roles in isolation membrane development.
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              New use of BCG for recombinant vaccines.

              BCG, a live attenuated tubercle bacillus, is the most widely used vaccine in the world and is also a useful vaccine vehicle for delivering protective antigens of multiple pathogens. Extrachromosomal and integrative expression vectors carrying the regulatory sequences for major BCG heat-shock proteins have been developed to allow expression of foreign antigens in BCG. These recombinant BCG strains can elicit long-lasting humoral and cellular immune responses to foreign antigens in mice.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                December 2010
                December 2010
                16 December 2010
                : 6
                : 12
                Affiliations
                [1 ]Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, Korea
                [2 ]Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, Korea
                [3 ]Department of Microbiology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea
                [4 ]Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea
                [5 ]Division of Life Science, Korea Basic Science Institute, Daejeon, Korea
                [6 ]Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America
                University of New Mexico, United States of America
                Author notes

                Conceived and designed the experiments: DMS BYJ CHS JMK RLF EKJ. Performed the experiments: DMS BYJ HML HSJ JMY CHS SHL JMK EKJ. Analyzed the data: DMS BYJ HML HSJ JMY CHS SHL ZWL JMK RLF EKJ. Contributed reagents/materials/analysis tools: BYJ CHS ZWL SNC JMK RLF EKJ. Wrote the paper: DMS BYJ RLF EKJ.

                Article
                10-PLPA-RA-3060R5
                10.1371/journal.ppat.1001230
                3002989
                21187903
                Shin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Categories
                Research Article
                Cell Biology/Cellular Death and Stress Responses
                Immunology/Innate Immunity
                Infectious Diseases/Bacterial Infections
                Microbiology/Cellular Microbiology and Pathogenesis
                Microbiology/Innate Immunity

                Infectious disease & Microbiology

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