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Review
. 2021 Mar 22:11:633360.
doi: 10.3389/fcimb.2021.633360. eCollection 2021.

Regulatory Mechanisms of Autophagy-Targeted Antimicrobial Therapeutics Against Mycobacterial Infection

Prashanta Silwal  1   2 , Seungwha Paik  1   2 , Jin Kyung Kim  1   2 , Tamotsu Yoshimori  3   4 , Eun-Kyeong Jo  1   2
Affiliations
Review

Regulatory Mechanisms of Autophagy-Targeted Antimicrobial Therapeutics Against Mycobacterial Infection

Prashanta Silwal et al. Front Cell Infect Microbiol. .

Abstract

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen causing human tuberculosis, an infectious disease that still remains as a global health problem. Autophagy, a lysosomal degradative process, has emerged as a critical pathway to restrict intracellular Mtb growth through enhancement of phagosomal maturation. Indeed, several autophagy-modulating agents show promise as host-directed therapeutics for Mtb infection. In this Review, we discuss recent progress in our understanding the molecular mechanisms underlying the action of autophagy-modulating agents to overcome the immune escape strategies mediated by Mtb. The factors and pathways that govern such mechanisms include adenosine 5'-monophosphate-activated protein kinase, Akt/mammalian TOR kinase, Wnt signaling, transcription factor EB, cathelicidins, inflammation, endoplasmic reticulum stress, and autophagy-related genes. A further understanding of these mechanisms will facilitate the development of host-directed therapies against tuberculosis as well as infections with other intracellular bacteria targeted by autophagic degradation.

Keywords: AMPK; Mycobacterium tuberculosis; autophagy; host-directed therapeutics; mTOR.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of xenophagy and LAP during Mtb infection. Xenophagy and LAP are activated in host cells during Mtb infection. (Left) Mtb that enters the host cells by phagocytosis can reside within phagosomes and resist fusion with lysosomes. The phagosome is then damaged by the ESX-1 system to induce Smurf1- and Parkin-mediated ubiquitination, thereby adaptor proteins such as p62 and NDP52 are recruited leading to formation of autophagosome. Also, Rv1468c, a surface protein of Mtb that escapes from the phagosome, induces xenophagy by binding with ubiquitin. In addition, the Mtb DNA exposed to the cytosol from the damaged phagosome is recognized by cGAS to induce xenophagy. Both the enhanced intracellular survival (Eis) gene of Mtb and putative Mtb lipoprotein LprE inhibit autophagy. Additionally, several miRNAs that inhibit xenophagy are shown in the context of mycobacterial infection. In addition, Mtb inhibits the recruitment of Rab7, thus disturbing the fusion of autophagosome and lysosome. (Right) Various PRRs recognize Mtb and invade the host cell. Rubicon complex (Rubicon-BECN1-VPS34-UVRAG) and NOX2-dependent ROS are important in the activation of LAP. In this process, LAPosome, a single membrane surrounded by LC3 is formed, which fuses with lysosome to eliminate Mtb. At this time, it is known that CpsA, a protein of Mtb, interferes with the LAP mechanism.
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