Moreover, treatment of rapamycin, combined with isoniazid, promote sterile clearance and prevention of TB reactivation (Fatima et?al., 2020). WHO, 2020). Autophagy functions as a cell-autonomous defensive pathway against intracellular Mtb (Gutierrez et?al., 2004; Kimmey et?al., 2015). After phagocytosis, a majority of Mtb resides in phagosome to escape the phagolysosomal acidification, but some of them access to cytosol and can be targeted by xenophagy (Watson et?al., 2012; Manzanillo et?al., 2013; Gomes and Dikic, 2014; Paik et?al., 2019). Chondroitin sulfate Indeed, a variety of agents triggering autophagy/xenophagy promote phagosomal maturation through autophagic capture of either intraphagosomal Mtb or cytosolic pathogens (Gupta et?al., 2016; Kim Y. S. et?al., 2019). In this Review, we outline the mechanisms underlying the effects of autophagy-based agents to enhance host defense against Mtb infection. In particular, we discuss the mechanisms and?signaling pathways (adenosine 5-monophosphate [AMP]-activated protein kinase [AMPK], mammalian target of rapamycin [mTOR] kinase, Wnt, transcription factor EB [TFEB], cathelicidins, inflammation, endoplasmic reticulum [ER] stress,?and autophagy-related genes [ATGs]) that would make autophagy-activating agents a potential host-directed therapeutic?(HDT) or alternative to current tuberculosis (TB) chemotherapeutics. Overview of Autophagy During Mycobacterial Infection Autophagy is a catabolic process of damaged cellular components to ensure cell survival and homeostasis (Glick et?al., 2010; Ryter et?al., 2013). There are three canonical autophagy pathwaysmacroautophagy, microautophagy, and chaperone-mediated autophagy, which differ in how the cargo is targeted and delivered to lysosomes (Glick et?al., 2010; Ryter et?al., 2013). Macroautophagy (hereafter referred to as autophagy) is activated by stress signals including starvation, hypoxia, and infections, and is characterized by the formation of double-membraned autophagosomes, which fuse with a lysosome to form an autolysosome, the site of cargo degradation (Glick et?al., 2010; Ryter et?al., 2013). Mtb has developed numerous strategies to avoid autophagic defense and manipulate host innate immunity (Jiao and Sun, 2019). For example, the ESX-1 system, Mtb suppresses the late-stage autophagy in human dendritic cells to escape dendritic cell-mediated immunity (Romagnoli et?al., 2012). The enhanced intracellular survival (Eis) gene of Mtb inhibits macrophage autophagy, at least partly mediated through suppression of c-Jun N-terminal kinase (JNK)-reactive oxygen species (ROS) signaling, in macrophages (Shin et?al., 2010a). Also, Mtb lipoprotein LprE inhibits autophagy and cathelicidin expression to favor bacterial replication during infection (Padhi et?al., 2019). In addition, virulent Mtb strains inhibit the recruitment of Rab7, the late endosomal/lysosomal protein, to the phagosomes, thereby escaping from phagosomal fusion with lysosomes (Chandra et?al., 2015; Chandra and Kumar, 2016). However, ATGs, except ATG5, in myeloid cells do not appear to be essential in the activation of host defense (Kimmey et?al., 2015). In addition, Mtb pathogens can epigenetically control host autophagy pathway through regulation of microRNAs (miRNAs) to favor mycobacterial replication in the host cells during infection (Batista et?al., 2020; Ruiz-Tagle et?al., 2020; Silwal NAV3 et?al., 2020). The miRNAs that are associated with pathogenesis of Mtb infection include miR-33/miR-33* (Ouimet et?al., 2016), miR-889 (Chen et?al., 2020), Chondroitin sulfate miR-18a (Yuan et?al., 2020), and miR-125a (Kim et?al., 2015), all of which are increased by Mtb infection; whereas others such as miR-26a (Sahu et?al., 2017) and miR-17-5p (Kumar et?al., 2016), both of which are decreased by Mtb infection. Numerous miRNAs that are involved in the regulation of autophagy in terms of host-pathogen interaction during Mtb infection have been extensively discussed elsewhere (Kim J. K. et?al., 2017; Sabir et?al., 2018; Yang and Ge, 2018; Silwal et?al., 2020; Sinigaglia et?al., 2020) and are not the focus of this Review. Thus, it remains to be fully characterized the exact mechanisms by which Mtb evade from host autophagic defense system, Chondroitin sulfate although several autophagy-activating drugs/agents are able to suppress Mtb growth and (Stanley et?al., 2014; Gupta et?al.,.