Autophagy as an innate defense against mycobacteria

Pathogens and Disease ISSN 2049-632X MINIREVIEW Autophagy as an innate defense against mycobacteria Eun-Kyeong Jo1,2 1 Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea 2 Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea A contemporary, comprehensive and timely review of autophagy in mycobacterial infections with particular relevance to tuberculosis. A review of this proportion supported by excellent figures has long been needed. Correspondence Eun-Kyeong Jo, Department of Microbiology, and Infection Signaling Network Research Center, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jungku, Daejeon 301-747, S. Korea. Tel.: 82-42-580-8243 fax: 82-42-585-3686 e-mail: Received 29 September 2012; revised 12 January 2013; accepted 13 January 2013. Final version published online 21 February 2013. doi:10.1111/2049-632X.12023 Abstract Over the past several years, much has been revealed about the roles of autophagy and the mechanisms by which the autophagic pathway activates the host innate effector response against Mycobacterium tuberculosis (Mtb) infection. In response to invading mycobacteria, the host innate immune system not only recognizes pathogen motifs through innate receptors, it also produces appropriate effector proteins, including cytokines. These innate signals activate or regulate autophagic pathways during infection. It is now clear that vitamin D and functional vitamin D receptor signaling are critical in the activation of autophagic defenses against Mtb in human cells. Immunity-related GTPase family M proteins, including the cationic antimicrobial protein cathelicidin and autophagic receptor p62, participate in autophagic pathways that enhance antimicrobial activity against mycobacteria. Moreover, reactive oxygen species mediate antibacterial autophagy and successful antimicrobial responses during antibiotic chemotherapy. Recent work has also shown that pathogenic Mtb can be targeted by selective autophagy through an ESX-1 type VII secretion system. Here, we review the triggers, host factors, and intracellular pathways that regulate host autophagy and its impact on antimicrobial host defenses during mycobacterial infection. Editor: Patrick Brennan Introduction Tuberculosis (TB) is one of the most devastating infectious diseases globally. It is estimated that around one-third of the population is latently infected. The WHO reported that there were an estimated 8–9 million TB cases in 2010. TB is the second leading cause of death caused by an infectious disease, with a death rate of 1.2–1.5 million worldwide (including deaths from TB among HIV-positive individuals). Serious concerns have been raised regarding an increase in the number of patients with MDR-TB (WHO, 2011). Autophagy is a ubiquitous intracellular process through which diverse cytoplasmic cargos are captured and destroyed to replenish amino acids and energy sources during metabolic stress. During the host response to intracellular parasites, autophagy plays two roles: effector and regulatory roles. During mycobacterial infection, autophagy is essential for mounting an effective host response (Gutierrez et al., 2004; Singh et al., 2006). If the Mycobacterium tuberculosis (Mtb) phagosome is not appropriately acidified through the selective exclusion of late 108 endosomal Rab7 (Via et al., 1997), it persists in immature phagosomes within host macrophages. Autophagy acts as an immune effector, resulting in phagosomal maturation that mediates mycobacteria clearance (Gutierrez et al., 2004). Interferon (IFN)-inducible effector proteins, including immunity-related GTPase family M (Irgm) proteins, play a host protective function against mycobacterial infection through IFN-c-induced autophagy (Singh et al., 2006). Additionally, human genetic approaches have identified Irgm gene variants that protect against Mtb infection (Intemann et al., 2009). Recently, vitamin D receptor (VDR), a nuclear receptor that mediates various biological functions of 1,25(OH)2D3 (1,25D3), has been found to play an essential role in antimycobacterial responses through the activation of autophagy (Liu & Modlin, 2008; Fabri & Modlin, 2009; Jo, 2010). Cargo receptors, including p62/SQSTM1, have been featured in selective autophagy through the connection of ubiquitinated intracytoplasmic cargos into autophagic machinery (Kirkin et al., 2009). Moreover, the roles of reactive oxygen species (ROS) in antibacterial autophagy Pathogens and Disease (2013), 67, 108–118, © 2013 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved Keywords mycobacteria; autophagy; vitamin D; cytokines; autophagy receptors; innate immunity. E.-K. Jo Overview of autophagy and innate immune receptors in mycobacterial infection Autophagy is a process for maintaining intracellular quality control in the face of various stressors that mainly play a housekeeping role. So far, three autophagic pathways have been identified: macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy (referred to as autophagy throughout this review) initiates the formation of a new vesicle, the phagophore, which is enlarged, elongated, and generated into a double-membraned organelle, the autophagosome. The autophagosome fuses with lysosomes, maturing into an autolysosome. Here, cytoplasmic cargos are degraded. This mechanism is recognized as an essential host defense mechanism able to eliminate bacteria in macrophages and nonphagocytic cells infected with numerous bacteria, including Streptococcus, Shigella, Legionella, and Salmonella typhimurium (Nakagawa et al., 2004; Amer et al., 2005; Ogawa et al., 2005; Birmingham et al., 2006). Various bacterial pathogens have evolved strategies to escape from or subvert host autophagy to persist in or invade host cells. Autophagy can also function as an innate effector and regulate innate immunity to various viruses and bacteria, €nz, including Mtb (Levine & Deretic, 2007; Schmid & Mu 2007; Yuk et al., 2012). Mtb is a successful intracellular pathogen that has evolved a successful strategy for evading host defenses by arresting phagosome maturation in infected host cells (Fratti et al., 2001; Vergne et al., 2004). The activation of autophagy induces co-localization of the mycobacterial phagosome with LC3 autophagosomes and delivers antimicrobial proteins to autolysosomal compartments, achieving enhanced bactericidal activity in phagocytes (Gutierrez et al., 2004; Singh et al., 2006). Understanding autophagy’s role in regulating innate immunity and vice versa will help elucidate the molecular basis of host defenses against mycobacteria (Fig. 1). During mycobacterial infection, toll-like receptor (TLR) signaling plays an important role in the recognition of pathogens and elicits an inflammatory response, including the production of cytoki (...truncated)