Dr. Sharee Basdeo

Tuberculosis (TB) is a leading cause of death from an infectious agent. Globally, there has been a marked increase in TB incidence and drug-resistant TB in the past two years. There is an urgent unmet clinical need for host-directed therapeutics and prophylactics capable of inducing effective respiratory immunity against the bacteria that causes TB; Mycobacterium tuberculosis (Mtb). Since the tissue resident alveolar macrophage (AM) is the first cell to encounter Mtb in the human lung, and the cell that becomes chronically infected leading to TB disease, supporting the immune function of this population, and the lung resident cells in proximity, is a rational therapeutic strategy to promote immune defence against Mtb infection. Myeloid cells from the bone marrow have a capacity to be `trained" towards enhanced host defence. Our recent work has shown that a COVID- 19 adenovirus-vectored vaccine 'trained' monocytes towards enhanced non-specific immune responses to Mtb. Our collaborator showed that aerosolised delivery of an adenovirus vectored vaccine against Mtb elicited immunity in the lung whereas intramuscular vaccination did not. Evidence from murine models of respiratory mucosal adenovirus vaccination indicates that murine AM can be 'trained' resulting in enhanced immunity to bacterial infection mediated by improved kinetics of myeloid cell recruitment. However, a significant knowledge gap human remains as to whether tissue resident human AM can be trained to promote immunity to Mtb, and the mechanisms inducing and propagating trained immunity in the human lung. This project will be the first to define the induction of trained immunity in human AM through evidence of functional and phenotypic changes in the human AM, underpinned by metabolic and epigenetic reprogramming. These crucial data will define the human AM as a critical target for respiratory mucosal prophylactic or therapeutic vaccination, enabling the translation of trained immunity towards the global effort to `End TB".

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.

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.