Novel adjunctive therapies for the treatment of tuberculosis

Abstract

Despite significant efforts to control tuberculosis (TB), the disease remains a major global threat, with an estimated 8.6 million new cases and 1.3 million deaths in 2012 alone. Significant treatment challenges include HIV co-infection, the dramatic rise of multidrug-resistant TB and the vast reservoir of latently infected individuals, who will develop active disease years after the initial infection. The long duration of chemotherapy also remains a major barrier to effective large scale treatment of TB. Significant advances are being made in the development of shorter and effective TB drug regimens and there is growing evidence that host-directed and "non-antimicrobial" pathogen-directed therapies, could serve as novel approaches to enhance TB treatments. This review highlights the rationale for using these therapies and summarizes some of the progress in this field.

Fig. 1. Formation of cavitary TB lesions

After deposition of M. tuberculosis in the alveoli via an airborne route, initial events include phagocytoses by alveolar macrophages, bacterial replication within macrophages, development of delayed-type hypersensitivity (DTH) and the formation of the TB granuloma. These initial microscopic TB granulomas are composed mainly of activated macrophages and lymphocytes and may often have multinucleated giant cells (also called Langhans giant cell) with nuclei arranged like a horseshoe. With the emergence of DTH, infected macrophages in the interior of the granuloma are killed, and the periphery becomes fibrotic due to the production of collagen by fibroblasts. The granuloma enlarges progressively to a macroscopic lesion with central areas of “caseous” necrosis, surrounded by activated macrophages, lymphocytes, and fibroblasts. Occasionally, the necrotic TB granuloma bursts into an airway to form a cavitary lesion. This process releases a large number of bacteria directly into the airway and patients with cavitary TB are highly infectious.

Fig. 2. Current model of TB treatment

Rapid bacterial killing is observed during the initial intensive phase which typically requires 4-drugs. However, the rate of killing is slower during the continuous phase due to “dormant” or “persistent” bacteria which are slowly or sporadically multiplying and therefore not amenable to effective killing by TB drugs. By targeting “dormant” or “persistent” bacteria, adjunctive therapies could hasten bacterial clearance (dotted line) and help in development of shorter and effective TB treatments.

Fig. 3. Mechanism of action of corticosteroids

Corticosteroids diffuse across the cell membrane and bind to intracellular receptors that translocate into the nucleus. This complex interacts with DNA, resulting in altered transcription of various corticosteroid-responsive genes. Corticosteroids have diverse physiological effects and directly or indirectly regulate several different immune cell as shown here. These actions are primarily accomplished by modulating inflammatory cytokines as well as through induction of apoptosis.