Role of apoptosis and autophagy in tuberculosis

Abstract

Tuberculosis (TB) is one of the oldest known human diseases and is transmitted by the bacteria Mycobacterium tuberculosis (Mtb). TB has a rich history with evidence of TB infections dating back to 5,800 bc TB is unique in its ability to remain latent in an individual for decades, with the possibility of later reactivation, causing widespread systemic symptoms. Currently, it is estimated that more than one-third of the world's population (~2 billion people) are infected with Mtb. Prolonged periods of therapy and complexity of treatment regimens, especially in active infection, have led to poor compliance in patients being treated for TB. Therefore, it is vitally important to have a thorough knowledge of the pathophysiology of Mtb to understand the disease progression, as well as to develop novel diagnostic tests and treatments. Alveolar macrophages represent both the primary host cell and the first line of defense against the Mtb infection. Apoptosis and autophagy of macrophages play a vital role in the pathogenesis and also in the host defense against Mtb. This review will outline the role of these two cellular processes in defense against Mtb with particular emphasis on innate immunity and explore developing therapies aimed at altering host responses to the disease.

Keywords: apoptosis; autophagy; endoplasmic reticulum stress; tuberculosis.

Fig. 1.

Role of apoptosis in mycobacterial tuberculosis (Mtb) infection. The major pathophysiological events that lead to either induction or inhibition of apoptosis in macrophages by the avirulent Mtb strain (H37Ra) and virulent Mtb strain (H37Rv) are summarized. Macrophages infected with H37Ra strain attain M1 phenotype, have predominantly smooth endoplasmic reticulum (ER), and have high levels of ER stress, resulting in increased apoptosis and Mtb death. However, macrophages infected with H37Rv strain attain M2 phenotype, have predominantly rough ER, and have comparatively lower levels of ER stress, resulting in the attenuation of apoptosis and improved Mtb survival.

Fig. 2.

Strategies to inhibit autophagy by mycobacterial tuberculosis (Mtb). The major strategies adopted by Mtb to combat bacterial death by autophagy are summarized. Mtb has evolved techniques to evade killing by autophagy, allowing unchecked bacterial growth. Macrophages infected with Mtb have upregulated IL-6 production, which selectively inhibits IFN-γ-induced autophagosome biogenesis. In addition, Mtb possess the “enhanced intracellular survival” (Eis) gene, which attenuates autophagy and improves Mtb survival. Finally, Mtb upregulates the microRNAs miR-23a-5p, miR-20a, and miR-33, which prevent the activation of autophagy by Mtb. Currently, there is not enough data in the literature to compare the role of autophagy in avirulent and virulent Mtb strains, as mentioned in Fig. 1 for apoptosis.