“It’s crucial to be able to distinguish between diseases with similar clinical manifestations like MAC disease and TB, in order to diagnose them correctly and provide relevant treatment. Winning a SPARK award would give me an opportunity to investigate this further and strengthen the potential to attract follow-on funding for this project.”
The fight against Mycobacteria
FUNDED: JANUARY 2020
FUNDED BY: the generosity of 2019-20 Various Donors
What was the goal of your SPARK project?
To control tuberculosis (TB), we need to understand the mechanisms of host resistance to the Mycobacterium tuberculosis bacterium (Mtb).
Non-tuberculous mycobacteria (NTM) are a group of over 140 mycobacterial species. For my SPARK project, I wanted to take a closer look at Mycobacterium avium complex (MAC), the NTM species that most frequently colonizes and infects humans. Some evidence suggests that MAC exposure varies in different geographic regions, which might explain the disparate outcomes of BCG vaccination (given where tuberculosis is common), as well as susceptibility to Mtb infection and TB. Despite their differences, MAC and Mtb are related and may have important structural similarities. These conserved “antigens” may induce similar T cell responses against MAC, TB and TB vaccines.
It has been traditionally hard to study these T cell responses due to a lack of reliable tools to measure MAC-specific immune responses in individuals. My initial goal was to identify reagents (T cell epitopes) to measure MAC-specific immune responses in the blood.
Pivoting during a pandemic
I was fortunate to finish cell sorting and RNA sequencing right before lockdown began in March 2020, and thus I could focus on the analysis working remotely. I adjusted my approach to also involve a technician in the bioinformatic analysis, so that she could continue to be productive despite not being able to do lab work.
What’s next for this project?
I found that MAC contains unique peptides and proteins not present in Mtb or other NTM, i.e. MAC-specific. However, T cell responses were low in all individuals with a history of MAC infection. Therefore, individuals with a history of MAC lung infection/disease do not respond with the same antigen-specific T cell responses seen in most patients with other infectious diseases. This finding suggests individuals with MAC disease may have other underlying immune deficiencies that predispose them to MAC infection. Importantly, my results further indicated that individuals with MAC infection do not have a general defect in the other arms of their immune response, only in their MAC-specific T cell response. This is because they mounted T cell responses against Epstein-Barr and cytomegalovirus comparable to other patient cohorts.
I also found that individuals with MAC disease have lower frequencies of a specific T cell subset known to fight mycobacteria (including NTMs and Mtb), which was also reflected in their specific gene signature. This adds evidence for a T cell deficiency in individuals with MAC disease, which explains the lack of conventional antigen-specific T cell responses. In fact, this could explain why these individuals were infected with MAC in the first place. Further studies will pinpoint the reason for this lack of a specific T cell subset.
What’s next for Cecilia?
In January 2020, I was promoted to Research Assistant Professor, which means I now have my own lab and independence in working on research projects at my own discretion. Through this new position, I hope to continue to develop my research program studying T cell responses in mycobacterial infections, including both tuberculosis and other mycobacteria. I also have an interest and a research program close to my heart studying autoimmune T cell responses in neurodegenerative diseases including Parkinson’s disease (which my dad is diagnosed with), Alzheimer’s disease, and ALS. As part of both of these research programs I thoroughly enjoy working with and mentoring technicians, grad students and postdocs.