M. tuberculosis is a rod-shaped acid-fast-staining bacterium of the Actinomycete family
[7]. The unique “waxy” cell envelope of
M. tuberculosis contains a core composed of peptidoglycan and the highly branched polysaccharide arabinogalactan. This is covalently attached to the unique mycolic acids that cover the bacteria with a mycobacterial outer membrane which allows cellular integrity and virulence
[8]. This self-protection permits the organism to evade the host immune system and prevents antibiotic penetration
[8][9][8,9]. The molecular pathology by which
M. tuberculosis evades the host and causes disease is complex, involving a dynamic range of immune cells. The organism infects the host after the inhalation of droplet nuclei spread by aerosolisation from an infected individual, which then resides in the respiratory tract
[10]. There are various types of infection that can manifest from
M. tuberculosis in individuals—one where the infection clears, one with an active infection treated with a course of antibiotics, and one which remains in a latent form
[11]. Upon infection, the early innate immune system emerges with an influx of neutrophils, monocytes, macrophages, and dendritic cells of the lungs
[12]. Through phagocytosis, bacteria are consumed by alveolar macrophages to form a phagosome and then subsequently eliminated through the formation of phagolysosomes
[13]. However,
M. tuberculosis can avoid this host defence response by persisting in phagosomes and inhibiting lysosome fusion
[13]. The subsequent established intracellular infection and influx of immune cells which surround the site of infection forms a tuberculous granuloma
[14]. The early granuloma (
Figure 1) consists of the infected macrophages in the centre, enclosed by foamy macrophages and other mononucleated cells, and surrounded by lymphocytes
[15]. During the maturation of the granuloma, a fibrous capsule encloses the macrophage centre and eventually forms necrotic lesions, leading to caseation
[14][15][14,15].
Here,
M. tuberculosis can survive in a dormancy state known as non-replicating persistence (NRP). The external pressures such as hypoxia, nutrient deprivation, low pH, and high CO
2 created by the hostile host environment induce this survival response of the bacteria
[16]. The NRP state can relapse into active disease, especially in high-risk groups such as immunodeficient individuals, persons infected with human immunodeficiency virus or undergoing organ and haematologic transplantations
[11]. Houben and Dodd (2016) previously estimated that NRP TB infected approximately 1.7 billion people in 2014 by generating an annual risk model of infection between 1934 and 2014
[17]. The issue posed by the ability of NRP
M. tuberculosis to effectively hide within the hostile environment of the granuloma is that not only does the immune system keep the bacteria trapped, it also physically restricts penetration by antimicrobials, thus protecting
M. tuberculosis from antibiotic activity.