Conclusions and Proposals for Future Work

The Next Steps

It will be crucial to determine how Mycobacterial tuberculosis within granulomas in order to develop more treatments for tuberculosis. Although genes that encode enzymes secreted by the bacterium in order to defend itself within granulomas has been determined, specific interactions have yet to be determined (Guirado et al. 2015). This is mostly due to the inability to recreate an environment for Mycobacterium tuberculosis that significantly resembles that of human granulomas (Guirado et al. 2015).

Perhaps one way to develop a human granuloma model would be to use stem cells. By introducing necessary genes, as well as transcription factors and promoters, into the stem cells that are found within macrophages, researchers could create the necessary environment for granulomas. By creating a 3-D model within a petri dish, similar to how Rudolph Tanzi and Doo Yeon Kim, and their team, created a 3-D human neural cell culture model, researchers could induce interactions between bacteria and macrophages (Choi et al. 2014).

Granuloma. Source:
Granuloma. Source:

It is incredibly important to reverse the suppression of immune response due to Mycobacterium tuberculosis defense mechanisms (Gong et al. 1996). Although interleukin-12 (IL-12) has been shown to be an effective method of reversing the effects of Mycobacterium tuberculosis on immune response, it is necessary to explore other avenues of reactivating the immune response (Gong et al. 1996).

A proposal for accomplishing this would be to decrease the amount of regulatory T cells that suppress immune response. Mycobacterium tuberculosis has been shown to increase the amount of regulatory T cells after infection (Wu et al. 2015). However, the mechanism by which this occurs has yet to be elucidated. Perhaps researchers could determine the how the molecules ESAT-6 and Ag85B secreted by the bacterium cause an increase in regulatory T cells. By discovering this, drugs could be develop that inhibit a pathway, or the molecules themselves, necessary for increased regulatory T cell production.

Due to the ability to restore lost cysteine residues necessary for Mycobacterium tuberculosis survival, it is imperative to determine how to disrupt this pathway (Ågren et al. 2008). Perhaps researchers could study the OPS-dependent pathway for the biosynthesis of cysteine (Ågren et al. 2008). By targeting different parts of the pathway, researchers could determine the most efficient way to disrupt it. Also, researchers could block the active site of CysM in order to prevent it from using the OPS-pathway. By further studying its structure, researchers may be able to find a molecule that would fit into the active site without being dislodged by OPS.

Cysteine Molecule. Source:
Cysteine Molecule. Source:

Concluding Thoughts

Although tuberculosis has been around for hundreds of thousands of years, it is still very prevalent around the world. It is imperative to continue research on how Mycobacterium tuberculosis interacts with its host’s environment to suppress immune response. Only when all of its metabolic pathways and biosynthetic defenses are discovered and elucidated will tuberculosis be efficiently and successfully treatable.

4 Replies to “Conclusions and Proposals for Future Work”

  1. Really nice job with your conclusions and proposals for future work. I like your point about modulating the over abundance of Tregs, which is a problem in several types of chronic infections.
    Do you think that treatments targeting cysteine metabolism would ultimately effect the ability of the bacteria to recruit constituents of granuloma formation?

    1. Thanks Dana! I really appreciate your feedback! I’m not sure if targeting cysteine metabolism will affect bacteria ability to recruit constituents of granuloma formation. Since the granuloma is causing oxidative stress and exposure to reactive nitrogen intermediates, cysteine residues and being targeted, thus causing the bacterium to use its cysteine-constituent reserve, mycothiol. By targeting the cysteine biosynthesis pathway, I don’t see how this would affect granuloma formation, since it is the granuloma that is driving the increase in cysteine biosynthesis. I hope this answered your question! Thanks again for your feedback!

  2. Very interesting post Nicole. It was interesting to learn more about latent TB as typically we only think about active TB. Reading your post it was really interesting some of the parallels in disease to Elliot’s project, Chronic Granulomota Disease. Are you aware of any studies that use the model of CGD as a means of understanding the formation of granulomas in the context of latent TB or vice versa?

  3. Hi Elaine! The studies I have come across really just look at the importance of ROS-derived phagocyte NADPH oxidase (NOX2) in the case Mycobacterium tuberculosis infection. Also, in children who develop tuberculosis, it seems as though it is also important to look to see if they also have CGD. However, I did not find any studies using a CGD model with tuberculosis, seeing as if NOX2 isn’t working, than there would obviously be a problem with immune response against Mycobacterium tuberculosis. I hope this answered your question!

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