Autophagy as a Target for Drug Development Of Skin Infection Caused by Mycobacteria

Abstract

Pathogenic mycobacteria species may subvert the innate immune mechanisms and can modulate the activation of cells that cause disease in the skin. Cutaneous mycobacterial infection may present different clinical presentations and it is associated with stigma, deformity, and disability. The understanding of the immunopathogenic mechanisms related to mycobacterial infection in human skin is of pivotal importance to identify targets for new therapeutic strategies. The occurrence of reactional episodes and relapse in leprosy patients, the emergence of resistant mycobacteria strains, and the absence of effective drugs to treat mycobacterial cutaneous infection increased the interest in the development of therapies based on repurposed drugs against mycobacteria. The mechanism of action of many of these therapies evaluated is linked to the activation of autophagy. Autophagy is an evolutionary conserved lysosomal degradation pathway that has been associated with the control of the mycobacterial bacillary load. Here, we review the role of autophagy in the pathogenesis of cutaneous mycobacterial infection and discuss the perspectives of autophagy as a target for drug development and repurposing against cutaneous mycobacterial infection.

Keywords: autophagy; drug development; mycobacteria; skin; skin cells.

Figure 1

Different steps of the autophagic pathway targeted by autophagy-modulating drugs. A schematic view of the different cell types populating the skin. Vertebrate skin is comprised of two major compartments: the epidermis and the dermis. The superficial part of the epidermis, known as the stratum corneum, is composed of dead keratinocytes and acts as a barrier. The epidermis is composed mainly of keratinocytes with few melanocytes. The major immune cells in this compartment include Langerhans cells (LCs) and CD8 T-cells. The dermis is composed of fibroblasts, NK cells, T-cells (CD4 αβ, and γδ), B cells, dermal dendritic cells, macrophages, mast cells, and neutrophils (non-exhaustive list). The knowledge of skin cell autophagy is mainly based in studies with dermal macrophages. Briefly, (1) autophagy is inhibited by mTOR and activated by AMPK. mTOR is inhibited by the autophagy-initiation signals as metabolic stress, ROS, infection and drugs, and leads to the activation of AMPK. After AMPK activation, the ULK1 complex (ATG13, ULK1/2, FIP200) initiates the phagophore formation (2), involving the targets (pathogens, dead cells, cellular components and organelles, protein aggregates), which in turn activates the Class III PI3K complex (Beclin 1, VPS34, VPS15, ATG14) (3). This complex completes the autophagosome maturation and elongation by forming PI3P in the omegasome membrane and recruiting downstream ubiquitin-like conjugation systems that convert LC3-I to LC3-II (4). Fully formed autophagosomes then fuse with lysosomes (autolysosomes), degrade the sequestered cargo via lysosomal hydrolases and recycle macromolecule components (5). Several drugs can interfere with the autophagic pathway by inhibiting or activating different parts of the process (see also Table 1 ). Drugs as rapamycin, resveratrol and nitazoxanide, that inhibit mTOR, or carbamazepine, metformin and pyrazinamide, that activate AMPK, induce autophagy. Bedaquiline, ambroxol and linezolid increase the formation of autophagosomes. Loperamide and valproic acid increase the colocalization of LC3-decorated autophagosomes with M. tuberculosis. Ibrutinib and isoniazid facilitate the fusion of phagosome and lysosome. Vitamin D3 (1,25D3) induces the expression of antimicrobial peptides as cathelicidin and upregulates the expression of Beclin 1 and ATG5, that are pivotal for the autophagosome formation. On the other hand, azithromycin was demonstrated to inhibit the acidification of the autolysosome impairing M. abscessus degradation.