Targeting Autophagy as a Strategy for Developing New Vaccines and Host-Directed Therapeutics Against Mycobacteria

Abstract

Mycobacterial disease is an immense burden worldwide. This disease group includes tuberculosis, leprosy (Hansen’s disease), Buruli Ulcer, and non-tuberculous mycobacterial (NTM) disease. The burden of NTM disease, both pulmonary and ulcerative, is drastically escalating globally, especially in developed countries such as America and Australia. Mycobacteria’s ability to inhibit or evade the host immune system has contributed significantly to its continued prevalence. Pre-clinical studies have highlighted promising candidates that enhance endogenous pathways and/or limit destructive host responses. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents, small molecules, and autophagy-activating vaccines may be beneficial in restricting intracellular mycobacterial infection, even with multidrug-resistant strains. This review will examine how mycobacteria evade autophagy and discusses how autophagy could be exploited to design novel TB treatment strategies, such as host-directed therapeutics and vaccines, against Mycobacterium tuberculosis and NTMs.

Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection

“… 60–62 NTM infections are often fatal in immunocompromised patients and treatment is particularly challenging because of multiple antibiotic resistance. 61 , 62 Importantly, we found that B. pseudolongum administration reduced in vivo bacterial loads during pulmonary infections with multidrug-resistant clinical strains of Mabc. Given the controversial findings of clinical trials investigating the efficacy of arginine supplementation upon TB outcomes, 28–30 our findings warrant further evaluation of gut microbiota composition in patients before treatment with arginine.…”

Autophagy and Host Defense in Nontuberculous Mycobacterial Infection

“…Moreover, anti-tumor necrosis factor (TNF)-α therapy during autoimmune diseases may lead to the increased risk of NTM diseases as well as tuberculosis, suggesting that TNF-α is also crucial for host defense against NTM infection ( 37 , 38 ). Recent studies highlight the function of autophagy and apoptosis as another key factor for controlling mycobacteria ( 1 , 3 ). In this review, we primarily discuss the current understanding of host cell autophagy in terms of host defense and controlling immunopathology during NTM infection.…”

“…In addition, several vaccine candidates with autophagy activation as a major element have been tested against Mtb in animal models ( 120 , 121 ), but there are currently no recommended vaccine protocols established to study the vaccine efficacy against NTM infections. Using autophagy-related strategies to develop effective vaccinations against NTM could be a huge advance in the fight against NTM infections ( 3 ). A schematic representation of the autophagy process during several NTM infections is shown in Figure 1 .…”

“…hominissuis, and M. intracellulare subsp. chimaera are the most common causes of NTM pulmonary diseases (NTM-PD), which are more emerging (1)(2)(3). Mycobacteroides abscessus (Mabc) is another frequently encountered pathogen that causes NTM-PD (4)(5)(6).…”

“…Recent studies highlighted multiple layered crosstalks of autophagy with several important processes, including innate immunity, immunometabolism, and mitochondrial function, to prevent harmful inflammation and to augment host protective function (10,11). Therefore, autophagy-activating strategies are becoming promising not only for the development of host-directed therapeutics but also for the design of potential vaccines against mycobacterial infection (3). However, intracellular pathogens are able to develop sophisticated strategies of exploitation and subvert autophagy in order to enhance their survival in the host cells (12)(13)(14).…”