Host-Directed Therapies for Tuberculosis

Abstract

Host-directed therapies are a relatively new and promising approach to treatment of tuberculosis. Modulation of specific host immune pathways, including those that impact inflammation and immunopathology, can limit mycobacterial infection and pathology, both in cell culture and in animal models. This review explores a range of host pathways and drugs, some already approved for clinical use that have the potential to provide new adjunctive therapies for tuberculosis. Drugs targeting host processes may largely avoid the development of bacterial antibiotic resistance, a major public health concern for tuberculosis. However, these drugs may also have generally increased risk for side effects on the host. Understanding the specific mechanisms by which these drugs act and the relationship of these mechanisms to Mycobacterium tuberculosis pathogenesis will be critical in selecting appropriate host-directed therapy. Overall, these host-directed compounds provide a novel strategy for antituberculosis therapy.

Figure 1.

Schematic of opportunities for host-directed therapies modulating eicosanoid balance. Clinically approved drugs that modulate eicosanoid production and that have been tested in animal models of mycobacterial infection are shown in boxes. Some drugs, such as aspirin, may act at multiple points in the eicosanoid pathway, whereas others, such as zileuton, may result in shunting effects. Bottom panel depicts human genotypes associated in a Vietnamese cohort with increased or decreased production of LTA4H and differential responsiveness to dexamethasone adjunctive therapy as well as a mouse model of disease in IL-1 pathway-deficient mice or animals with elevated type I interferons.