Tuberculosis is an infection that is caused by the bacterium Mycobacterium tuberculosis (MTB) and most often affects the lungs (CDC Basic TB Facts). It infects a third of the population worldwide, and in 2014, tuberculosis infected 9.6 million people, killing 1.5 million (CDC Basic TB Facts). MTB is spread through the air via breathing, coughing, sneezing or speaking (CDC Basic TB Facts). Due to this, tuberculosis is highly contagious when it is in the active form, however it cannot be passed on to someone else if it is in the latent form (CDC Basic TB Facts).
MTB can remain dormant so that signs and symptoms remain unexpressed (CDC Basic TB Facts). The problem arises when the MTB becomes active. Many people can live for years with latent tuberculosis without knowing, so it is important to get tested so it can be treated if necessary in order to prevent MTB from becoming active (CDC Basic TB Facts).
The reason why MTB can remain dormant in the lungs is because the body’s immune response has been found to be ineffective when combatting this pathogen. Research has shown that this is due to MTB inducing an increase in interleukin-10 (IL-10), which decreases the production of gamma interferon (Gong et al. 1996). Since gamma interferon is essential for innate immunity, the low levels of gamma interferon caused by MTB infection depress the immune response. The importance of gamma interferon was seen earlier in 1993. An experiment was conducted wherein mice that were gamma interferon-deficient were subjected to MTB, and began to experience extreme liver and spleen necrosis (Flynn et al. 1993).
Another way in which the immune response is ineffective towards MTB is through the disruption of T cell homeostasis. The regulatory T cells CD4+ and CD25+ express the forkhead box P3 (FOXP3), which is essential for maintaining T cell homeostasis and controlling immune response. The percentage of of these regulatory T cells, as well as messenger RNA (mRNA) expression of FOXP3, has been shown to be higher in patients being treated for active tuberculosis when compared to untreated patients with latent tuberculosis. However when grown with MTB secreted antigens ESAT-6 or Ag85B, these regulatory T cells expanded and generated, throwing off the balance, thus inhibiting immune response (Wu et al. 2014).
Effector T cells can also have a hard time mounting an attack against MTB due to an increase in apoptosis of these cells. In a study performed in 2015, it was determined that T cells from patients who tested positive for latent tuberculosis underwent apoptosis at a higher rate than T cells from those who tested negative for latent tuberculosis. Also, it was shown that there was a decrease in the expression of anti-apoptotic genes in latent tuberculosis positive patients than negative ones. Therefore, T cells are dying before they are able to successfully combat MTB (Elliot et al. 2015).
Due to the multiple ways in which MTB can defend itself from the body’s immune response, latent tuberculosis can persist, thus it is important to combat these defenses. The possibility for multiple drug therapies for latent tuberculosis has come to light in numerous experiments that have been conducted. One of the ways in which this has been done is by investigating biosynthetic pathways used by MTB. The biosynthesis of cysteine by MTB is important for its oxidative defense against immune responses. CysM, a cysteine synthase, was previously shown to use O-acetyl-L-serine as a sulfur acceptor in its metabolic pathway. However, is has been determined that another component of the pathway, O-phosphoserine, is also used by CysM as a sulfur acceptor. The development of drug therapies that target not only one part of MTB’s cysteine biosynthetic pathway, but multiple parts, could possibly combat oxidative defense against immune response (Ågren et al. 2008).
It is important to continue research on latent tuberculosis and MTB because it can greatly withstand the body’s immune response. By finding other sources for its defense mechanism, as well as determining other methods of detection, target drug therapies can be developed in order to combat MTB and latent tuberculosis in order to prevent it from becoming active.
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