Autophagy Induction as a Host-Directed Therapeutic Strategy against Mycobacterium tuberculosis Infection

Abstract

Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

Evaluation of Host Protein Biomarkers by ELISA From Whole Lysed Peripheral Blood for Development of Diagnostic Tests for Active Tuberculosis

“…CALCOCO2 plays a similar role in that it functions as a receptor for ubiquitin-coated bacteria and plays an important role in innate immunity by mediating macro-autophagy (52)(53)(54). This suggests a role in targeting TB bacilli for degradation by the innate immune system (54)(55)(56), which TB has evolved strategies to evade (57,58). However, increased CALCOCO2 expression may be a double-edged sword as it also targets the signalling adaptor MAVS for ubiquitination and autophagic degradation, hence inhibiting DDX58-mediated type I interferon signalling through a negative feedback loop (59).…”

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets

“…Notably, studies have shown that enhancing phagocytosis can effectively limit the intracellular growth of Mtb 343,344 . Phagocytosis serves as the fundamental link between the innate and adaptive branches of the immune system 345 .…”

Insights into innovative therapeutics for drug-resistant tuberculosis: Host-directed therapy and autophagy inducing modified nanoparticles

“…Trehalose is a naturally occurring disaccharide composed of two D-glucose molecules connected by glycosidic linkage, with the α, α-1,1-trehalose form being the most common in living organisms ( Adikesavalu et al, 2021 , Vanaporn and Titball, 2020 ). Trehalose is a vital carbon source for many bacteria and can support bacterial development; therefore, it plays a crucial function in protecting bacteria from various stressors ( Vanaporn and Titball, 2020 ).…”