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’.