How Tuberculosis is Spread
Mycobacterium tuberculosis is most often spread through coughing (Li et al. 2002). The bacteria travels through the air in droplets from the patient’s infected lungs to the recipient’s respiratory tract (Li et al. 2002). When the bacteria reach the alveolar cells, they secrete virulence determinants that are affected by host environmental conditions (Li et al. 2002). Furthermore, host environment determines the efficiency of the bacteria entering macrophages (Li et al. 2002).
The Granuloma Model
Granulomas are organized clusters of macrophages and epithelial cells surrounded by T cells (Guirado et al. 2015). The role of granulomas are to contain Mycobacterium tuberculosis in a specific area (Guirado et al. 2015). Since the bacteria possess defenses for its survival, it cannot be completely killed within granulomas, which is why latent tuberculosis can persist within the host (Guirado et al. 2015).
When developing drugs in order to treat tuberculosis, it is important to target metabolic pathways that support the bacteria’s defense against host immune response. The biosynthesis of cysteine is crucial to bacterium survival in granulomas (Ågren et al. 2008). It had previously been thought that latent tuberculosis can survive in granulomas due to its ability to fight oxidative stress and reactive nitrogen species by producing mycothiol (Schnell and Schneider 2010). Mycothiol contains important constituents of cysteine, which are used to synthesize it (Schnell and Schneider 2010). When oxidative stress and reactive nitrogen intermediates target cysteine residues, Mycobacterium tuberculosis can still survive due to mycothiol’s cysteine-constituent reserve (Ågren et al. 2008 and Schnell and Schneider 2010). One of these constituents, O-acetyl-L-serine (OAS), was thought to be the sulfur acceptor of CysM during the biosynthesis of cysteine in Mycobacterium tuberculosis (Ågren et al. 2008). It was thought that by targeting OAS, Mycobacterium tuberculosis would not be able to stabilize the amount of cysteine necessary for survival (Ågren et al. 2008). However, it was discovered that CysM uses another sulfur acceptor, O-phosphoserine (OPS), which utilizes a different pathway for synthesizing cysteine (Ågren et al. 2008).
Between the two substrates of CysM, OAS and OPS, it was determined that OPS allows for the rapid production of an aminoacrylate intermediate, which is part of the first half-reaction in the biosynthesis of cysteine (Ågren et al. 2008). It was also determined that the second order rate constant for this half-reaction was 600x greater when CysM donated sulfur to OPS when compared to CysM donating sulfur to OAS (Ågren et al. 2008).
Once a crystal structure was determined for CysM, the active site provided evidence for CysM’s preferential interaction with OPS (Ågren et al. 2008). An arginine residue within the active site was shown to specifically recognize OPS as a substrate (Ågren et al. 2008). Before the discovery of an OPS-dependent pathway, it was thought that Mycobacterium tuberculosis used OAS for cysteine biosynthesis (Ågren et al. 2008). However, with this additional pathway, drug therapies used to target the OAS-pathway do not completely inhibit bacterium survival (Ågren et al. 2008). Thus, the additional targeting the OPS-pathway for cysteine biosynthesis will provide further survival inhibition, making this a landmark experiment (Ågren et al. 2008).
Defense Against Immune Response
What makes tuberculosis such a deadly infection is that Mycobacterium tuberculosis can suppress host immune response (Wu et al. 2015). There are various components of the immune response that are affected by Mycobacterium tuberculosis, thus providing multiple defenses. One of the major ways in which this bacterium fights against immune response is by decreasing type 1 helper T cell (Th1) response and reducing interferon-gamma (Gong et al. 1996). This is accomplished through the production of interleukin-10 (IL-10) by phagocytes, which is induced by the bacterium (Gong et al. 1996). IL-10 inhibits the production of interleukin-12 (IL-12), which elicits the production of interferon-gamma and increases CTLA-4 expression (Gong et al. 1996). By decreasing the production of interferon-gamma, macrophage activity will greatly decrease (Flynn et al. 1993). Therefore, Th1 response will be suppressed, thus enabling Mycobacterium tuberculosis to persist in its host (Gong et al. 1996).
Recently, it has been shown that patients of tuberculosis have heightened levels of CD25+, CD4+, and FOXP3+ regulatory T cells (Wu et al. 2015). Antigens ESAT-6 and Ag85B secreted by Mycobacterium tuberculosis cause an increase in these regulatory T cells, thereby suppressing effector T cell activity (Wu et al. 2015). Furthermore, it has been shown that T cells undergo higher levels of apoptosis in patients with tuberculosis compared to those not infected (Elliot et al. 2015). Therefore, the bacterium can cause a decrease in host immune response (Wu et al. 2015).