Figures

Figure 1. The Host-Pathogen Interactions as Basis for Host-Directed Therapy Strategies for the Treatment of Mtb Infections.
Initiation of the host innate immune response occurs shortly after inhalation of aerosols containing Mtb bacteria and Mtb implantation in macrophages. Both resident and activated macrophages stimulates the release of pro-inflammatory cytokines, such as TNF-α and IL-1β, following phagocytosis and autophagy. Antigen presenting cells (macrophages and dendritic cells) that drain into local lymph nodes activate CD4+ and CD8+ T-cell mediated adaptive immune responses. Antigen presenting cells also stimulate the release of IL-12, which helps recruit additional CD4+ T-cells. CD4+ T-cells secrete IFN-γ that stimulates macrophage activation, IL-2, TNF-α, and also IL-10 that helps balance the pro-inflammatory response by deactivation of macrophages. CD8+ cells have cytotoxic activities. CD4+ T-cell secreted IL-2 drives further proliferation of CD4+ as well as CD8+ T-cells. Autophagic pathways start with parting of a section from endoplasmic reticulum, the phagophore, followed by the elongation of phagophore with engulfment of Mtb, autophagosome formation and maturation, and fusion of the autophagosome with lysosomes. Mtb activates mTORC1 and thus inhibits autophagy, while mTORC1 activates aerobic glycolysis. Intracellular cholesterol inhibits LC3, Ca2+, and LAMP3, and thus inhibits autophagy mediated Mtb killing. Mtb activates HDAC pathway and thus downregulates various genes responsible for innate and adaptive immune response.
Potential host-directed therapy strategies are presented in green text.