102 Exp. Mol. Med. Vol. 44(2), 99-108, 2012 Figure 1. The role of autophagy in control of innate immunity and the survival mechanisms of intracellular bacteria. Various intracellular bac- teria are internalized by phagocytes; these survive in the cytosol or phag- osome through various strategies. (1) First, some bacteria are able to escape from the phagosome by se- creting factors and replicating in the host cytoplasm (left panel). When autophagy is induced, Listeria mon- ocytogenes and Rickettsia conorii present in the cytoplasm are cap- tured by the autophagosomal mem- brane and degraded by the autoly- sosome; however, Shigella flexneri has the ability to avoid import into the autophagosome. (2) Second, some bacteria reside in the phag- osomal compartment (right panel). Upon autophagy activation, phag- osomes containing Mycobacterium tuberculosis are caught by the auto- phagic vacuole and then degraded by fusion with the lysosome. In con- trast, Brucella abortus and Legionella pneumophila can inhibit autophago- some maturation through inhibition of lysosome fusion, allowing the pathogen to survive and replicate. immune cells during bacterial infection (Cooper et al., 2011; Deretic, 2011). Notably, several cytokines are key regulators of autophagy pathways (Deretic 2009). For example, the Th1 cytokine IFN-γ is essential for host defense against intracellular pathogens. IFN-γ can overcome the blocking of phagosomal maturation induced by M. tuberculosis through autophagy activation (Gutierrez et al., 2004; Harris et al., 2009). In contrast, the T helper (Th) 2 cytokines IL-4 and IL-13 contribute to inhibition of autophagy and autophagy-mediated suppression of mycobacteria in macrophages (Harris et al., 2007). The mechanisms by which IFN-γ activates autophagy are: IFN-γ activates several anti-bacterial proteins involved in autophagy, such as IRG (p47 GTPases) and the 65-kilodalton (kD) guanylate- binding protein (Gbp) gene family members (Gbp1, Gbp6, Gbp7, and Gbp10). The IRG proteins (p47 GTPases), transcription of which is induced by IFN-γ stimulation, play an essential role in the elimination of intracellular pathogens in mice (Deretic, 2009). Murine IRG proteins are involved in innate defense against M. tuberculosis and Toxoplasma gondii (Gutierrez et al., 2004; Ling et al., 2006). Although the single human IRG member, IRGM, is not induced by IFN-γ, it is essential for induction of autophagy in response to intracellular bacterial infection (Singh et al., 2006). Moreover, recent studies have revealed that the Gbp gene family members (Gbp1, Gbp6, Gbp7, and Gbp10) are involved in oxidase-dependent killing and autophagy pathways in phagocytes to combat listerial or mycobacterial infection. Thus, 65-kD Gbps function to coordinate a potent oxidative and vesicular trafficking program to protect the host from infection (Kim et al., 2011). Reciprocally, autophagy facilitates IFN-γ-activated Jak2-STAT1