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Today’s science becoming tomorrow’s medicine: Dr Donal Cox describes the quest for new effective therapies for tuberculosis

Today is World Tuberculosis (TB) Day – commemorated to raise awareness about the devastating health, social and economic consequences of TB, and to step-up up efforts to end the global TB epidemic. TB remains one of the world’s most deadly infectious killers, with more than 4,100 people losing their lives worldwide each day. To coincide with World TB Day, we spoke to Dr Donal Cox, a post-doctoral researcher in Professor Joseph Keane’s Tuberculosis Immunology Research Group, Department of Clinical Medicine, Trinity Translational Medicine Institute (TTMI), based in St James’s Hospital.

Could you describe your research topic?

Mycobacterium tuberculosis (Mtb) is the causative agent for TB. It is estimated that one third of the world’s population is infected with Mtb, moreover TB is one of the top ten causes of mortality worldwide. While the Bacillus Calmette-Guérin (BCG) vaccine has been in use for almost 100 years, it does not provide lifelong immunity, and we do not have a successful vaccine against lung disease. There is still a lot that we don’t know about how our immunity works against Mtb. Furthermore, it is concerning that multiple new TB strains are emerging that are resistant to multiple antibiotic therapies. We are interested in host-directed therapies which enhance our immune system, rather than traditional therapies (like antibiotics) which target the bacteria itself. One of the most efficient and cheapest options for scientists is to repurpose drugs therapies which are already approved (and therefore known to be generally safe).

Has your laboratory had success in repurposing traditional drugs for TB?

Our group has demonstrated that already approved drugs such as Vorinostat and Desferrioxamine can augment and bolster the human immune response against Mtb. We are currently investigating how Dexamethasone (a steroid) may be used to help treat TB. Corticosteroids are currently the only approved adjunctive treatment against TB, where infection involves not only the lungs but also the brain.

Host directed therapies may be able to improve the metabolic function of patient’s immune cells. We have identified that the metabolic function is altered in the immune cells of people who are susceptible to Mtb (like macrophages of those who smoke and, more recently, the immune cells of new-born babies). Additionally, we have found that lactate (which was once regarded as a waste product of metabolism) might actually play a role in killing Mtb. Finally, we are currently investigating whether cytokine therapies might be able to fine tune the metabolic response of immune cells in the lung, therefore improving their ability to fight infection.

Do you work directly with patients?

As part of our research, we rely on the participation of patients attending St. James’s Hospital, Dublin to donate cells. Patients undergoing bronchoscopy donate the wash fluid from the procedure, from which we can isolate the most important immune cell for TB research, the alveolar macrophage. Patients with TB also donate blood to our studies allowing us to examine the influence of Mtb on the immune system, as well as testing new therapies in the lab.

How do you see your work impacting health?

We hope to identify new therapies which target the human immune response to help it combat Mtb after infection. By using primary human cells to identify novel functions for traditional drugs against Mtb, we hope that this will accelerate the development of new anti-TB therapies, giving greater chances of success in preclinical models and clinical trials.

Can you describe your day-to-day role within the team?

Our research is led by Professor Joseph Keane, a thought leader in the future of TB treatment. As part of Professor Keane’s research group, I am currently supervising a very talented medic Dr Lorraine Thong, who is doing her PhD on “Modulating Metabolism with Dexamethasone during Mycobacterium Tuberculosis Infection”. My own project focuses on the role of cytokines (namely IL-4 and Interferon-γ) in regulating the metabolic response of alveolar macrophage to infection. Specifically, my research is focused on restoring the ability of smoker’s macrophages to respond appropriately to Mycobacterium tuberculosis. To do this I use a state-of-the-art metabolic flux analyzer, Seahorse XFe24, housed in TTMI.

How did you come to join this team?

I joined Professor Keane’s research group in 2016 after my PhD which focused on brain macrophages called microglia. My research during this time focused on the role microglia in responding to infections and self-DNA in the Central Nervous System. I have always been interested in the innate immune response to infectious diseases, so Professor Keane’s group has really been a fantastic place to work during the COVID-19 pandemic.

What are your future goals?

My future research goals are to understand the molecular mechanisms underpinning defects in the innate immune response to microbes. My hope is that by working on human immunology I will be able to develop new therapies which will be crucial to combating both the increasing incidence of antibiotic resistance in bacteria, as well as the emergence of new pathogens.

What do you do when you are not researching TB?

When I’m not researching TB, I’m a huge fan of cooking and baking, when I have the time. Other than that, a good documentary on Netflix and My Nintendo Switch take up the rest of my spare time.

To learn more about World TB Day, visit https://www.who.int/campaigns/world-tb-day/2022