Host-Directed Therapies for Tuberculosis

Abstract

Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, the development of new TB treatment strategies is urgently needed. In this context, we present host-directed therapy (HDT) as an alternative to current tuberculosis therapy. Unlike antitubercular drugs that directly target Mycobacterium tuberculosis (Mtb), the causative agent of TB, HDT is an approach for treating TB that appropriately modulates host immune responses. HDT primarily aims to enhance the antimicrobial activity of the host in order to control Mtb infection and attenuate excessive inflammation in order to minimize tissue damage. Recently, research based on the repositioning of drugs for use in HDT has been in progress. Based on the overall immune responses against Mtb infection and the immune-evasion mechanisms of Mtb, this review examines the repositioned drugs available for HDT and their mechanisms of action.

Keywords: Mycobacterium tuberculosis; drug repositioning; host-directed therapy; tuberculosis.

Figure 1

Types of immune cells that contribute to the innate or adaptive immune responses against Mtb infection. Macrophages, neutrophils, and DCs of the myeloid lineage and NK cells of the lymphoid lineage are typically involved in innate immunity against Mtb infection. Specialized phagocytes, macrophages, neutrophils, and DCs can ingest Mtb to eliminate it. When NK cells recognize Mtb-infected cells, they secrete granzyme and perforin inside the granules and induce cell death in infected cells. Because macrophages and DCs also function as antigen-presenting cells, they migrate to the secondary lymphoid organ after phagocytosis and present antigens to CD4⁺ T cells, initiating adaptive immunity. Mtb-specific T cells primarily differentiate into Th1 or Th17 cells that secrete IFN-γ or IL-17, respectively, affecting immune responses against Mtb infection. However, the effect of Th17 cells on immune responses to Mtb remains controversial. Similar to NK cells, Mtb-specific CD8⁺ T cells recognize infected cells and secrete granules, inducing cell death. Humoral immunity associated with B cells and antibodies reportedly contributes to immune responses against Mtb infection, but this process is not yet fully understood.

Figure 2

Responses of macrophages to Mtb infection. (A) Macrophages ingest Mtb invaded by phagocytosis. Mtb-containing phagosomes become late phagosomes from early phagosomes through phagosome maturation, and they then fuse with lysosomes to eliminate Mtb inside the cell. Although the phagocytosis of macrophages essentially removes pathogens, phagocytosis may be a mechanism that provides refuge to Mtb because Mtb can inhibit phagosome maturation via its virulence factors and can proliferate inside macrophages. (B) When macrophages recognize Mtb through PRRs, downstream signaling is triggered and transcription factors are activated, promoting the expression of cytokines and chemokines. Cytokines mediate inflammatory responses, contributing to the control of Mtb infection, and chemokines are responsible for recruiting other immune cells to the infection site. In addition, macrophages produce ROS and RNS, and these reactive chemicals are involved in clearing Mtb inside phagosomes. Inflammation is essential to control pathogen invasion; however, unregulated inflammatory responses due to excessive cytokines cause tissue damage to the host. Thus, the balance of inflammatory responses is crucial in the control of Mtb infection. (C) Macrophages, which are antigen-presenting cells, can process phagocytosed Mtb and present its antigen. Macrophages that have ingested Mtb migrate to the secondary lymphoid organs and present antigens to CD4⁺ T cells, triggering adaptive immunity. (D) Mtb inside phagosomes can penetrate the phagosome membrane through ESX-1, a virulence factor of Mtb, and be exposed to the cytosol. Autophagy is a mechanism that can eliminate these cytosol-exposed Mtb. Autophagy starts with a phagophore, forms an autophagosome, and then fuses with the lysosome, forming an autophagolysosome. Mtb inside the autophagolysosome is removed by the degradative enzymes of the lysosome. (E) Mtb infection promotes the M1 polarization of macrophages. In M1 macrophages, the expression of enzymes associated with the TCA cycle is downregulated, stopping the TCA cycle, and metabolism switches mainly to aerobic glycolysis. Succinate accumulated by the cessation of the TCA cycle stabilizes HIF-1α, and HIF-1α contributes to controlling Mtb infection by promoting the expression of proinflammatory cytokines, among other mechanisms. However, citric acid also accumulates owing to the cessation of the TCA cycle, and excessive citric acid is converted to acetyl-CoA in the cytosol and is involved in the lipid accumulation of macrophages. (F) Mtb inhibits the fatty acid oxidation of macrophages and causes an accumulation of lipid droplets in the cytosol. Foamy macrophages with an excessive accumulation of lipid droplets lose their ability to control Mtb, and Mtb can exploit lipid droplets inside foamy macrophages as a nutrient. (G) Mtb-infected macrophages undergo various types of cell death. These types of cell death can be divided into non-necrotic cell death (apoptosis) and necrotic cell death. Apoptosis is useful to prevent the propagation of Mtb or to clear Mtb because the membrane is intact during apoptosis. Conversely, necrotic cell death is a membrane-rupturing form of cell death, allowing Mtb to easily spread to neighboring cells. Furthermore, because intracellular materials are leaked during necrotic cell death, inducing inflammatory responses and damage to proximal tissues, necrotic cell death is harmful to the host. Blue text indicates processes that are generally beneficial to the host. Red text indicates mechanisms that are usually exploited by Mtb. Black text indicates mechanisms that generally have two-sided effects.