Dr. Sharee Basdeo

Summary

Tuberculosis (TB) ranks alongside HIV as the world's most deadly infectious disease, killing 1.5 million people every year. It is caused by the bacteria Mycobacterium tuberculosis (Mtb), which primarily infects people's lungs. Treating this disease is becoming more difficult due to antibiotic-resistant Mtb, therefore, scientists are developing ways to boost the immune system to kill Mtb more effectively. Two immune cells that play a prominent role in our ability to fight Mtb are alveolar macrophages (AM) and T cells. AM are the guardians of the lungs and encounter the bacteria first. They try to contain infection by eating and killing the bacteria, and then switching on T cells. However, Mtb can manipulate the AM and live inside it, causing TB disease. T cells are the generals of the immune system, helping to coordinate long term defence. However, in TB, these cells can be a double-edged sword; sometimes they can help clear the infection, but they can also cause collateral damage to the lungs. It was recently discovered that AM can be "trained" to increase their functions (similar to the way training improves an athlete's performance). This improves the AM's ability to kill bacteria. In addition, we have evidence to suggest this training will give clearer signals to the T cells, which will balance the immune response towards clearing the infection, rather than damaging the lungs. This project will compare different training regimens to see which best promotes the killing of Mtb and what affect the training has on T cell responses. By studying the different types of T cells that are activated during Mtb infection, we will determine which response may be harmful to the patient. By better understanding the human immune response during Mtb infection, we will be able to adjust it to help the patient recover from TB.

Funding Agency

Health Research Board

Programme

Emerging Investigator Award

Person Months

12

Summary

The Problem Tuberculosis (TB) is a complex disease caused by a bacteria called Mycobacterium tuberculosis (Mtb) and claims the lives of 1.4 million people annually. When a person is exposed to Mtb, their immune response may clear the infection asymptomatically, contain it in a dormant state (called latent TB) or it can grow and replicate inside the macrophage causing active TB disease. The gap in our knowledge TB doesn't play by the rules of the immunity to infection. If you have previously had active TB you are more likely to get sick again with TB than someone who has never had it before and we don't know why. Our proposed solution Our research team study the innate immune response to Mtb and have established ways to therapeutically boost a patient's own immune system to fight off the bug. We think that Mtb may alter the function of the innate immune response long term in people who have previously had TB. This altered function is a bit like a scar that is left after an injury and we propose that this may be the reason why people who have had TB are more vulnerable to getting TB again. We want to define the status of innate immune cells in people who have had TB compared with healthy people in order to determine if their innate immune responses are reprogrammed by the infection. This will enable us to design a therapy aimed at protecting these vulnerable people from contracting TB again.

Funding Agency

Health Research Board

Programme

Investigator led project

Person Months

6

Summary

Funding Agency

Enterprise Ireland

Programme

ERC Support

Person Months

3

Summary

Funding Agency

TCD

Programme

Dean's Research Initiatives Award

Person Months

3

Summary

The immune responses in the lung tread a tightrope between mounting defensive inflammation against pathogens and maintaining the integrity of the delicate mucosal barrier. T cells play a crucial role in balancing appropriate and inappropriate inflammation and can exhibit a range of distinct behaviours in the lung. Therefore, the immune responses of T cells that live long term in the lung are thought to be important to the outcome of a pulmonary infection. Research largely focuses on the aberrant behaviour of immune cells in disease settings; however, it is becoming increasingly evident that there is paucity of information around what constitutes a healthy immune response in the lung. This project will focus on a population of T cells called Th17 cells which display extensive diversity and adaptability by exhibiting a spectrum of behaviours depending on the context of the immune response and the signals in the microenvironment. These cells have been implicated in lung pathologies including autoimmunity and infection leading to chronic inflammation. However, discreet members of this lineage are also known to be protective at mucosal sites. We hypothesise that Th17 lineage cells in healthy lungs maintain the integrity of the mucosal barrier and strike a balance in the immune response they generate and propagate through the complex cellular network of the lung tissue. However, these cells also have the ability to switch into more proinflammatory effector cells that cause damage and propagate intractable inflammation. This project aims to understand the behaviours of Th17 lineage cells that balance appropriate inflammation with maintaining barrier integrity in healthy lungs. We will examine the effects of the lung environment on human Th17 lineage cells using established in vitro models. In addition, we will determine the effects of Th17 lineage cell subpopulations on the lung environment, including their differential ability to propagate inflammation versus promoting resolution. Finally, this project will reuse existing data sets generated from human lung samples to determine a role for Th17 lineage subpopulations in mounting effective versus pathological immune responses in the lung. This project has the potential to create actionable knowledge in diverse contexts of respiratory diseases. Furthermore, it may contribute valuable understanding of how Th17 lineage cells behave in the lung and the signals promoting them to establish long term tissue resident memory cells that can mediate appropriate protection against infections. These data may therefore help to inform the design of inhaled vaccines for respiratory infectious diseases.

Funding Agency

TCD

Programme

Provost's PhD Project Awards

Project Type

PhD

Person Months

12