Tuberculosis (TB) remains a major global health burden; causing 10 million people to become ill and the death of 1.4 million people every year. A person that has had active TB is at increased risk of contracting active TB again, especially in the succeeding their cure, whereas people that have had latent TB and healthy controls have a lower risk of developing active TB.
Trained immunity is a functional reprogramming of innate immune cells which is induced by a primary insult, where innate immune cells are activated and then return to homeostatic function but maintain the epigenetic and metabolic reprogramming caused by the primary insult. This reprogramming results in an altered response to a subsequent insult.
This project will define if trained immunity is a feature of TB after a patient is cured and if this reprogramming of innate immune function is associated with increased susceptibility to contracting active TB upon reinfection. This will be determined by establishing the differential immunometabolic and epigenomic profiles of monocytes and macrophages from people who have recently recovered from active TB compared with healthy controls and people who have had latent TB infection. Moreover, the phenotypic and functional profiles of monocytes and macrophages from these cohorts will be established ex vivo and post in vitro restimulation to model a reinfection scenario.
We have previously established ways to therapeutically target epigenetic and metabolic function during Mtb infection in human macrophages. We will now target epigenetic and metabolic reprogramming to support host defence in people recently recovered from TB. These data will generate actionable knowledge towards the repurposing of epigenetic drugs or the design of novel drugs to use as host-directed therapies to protect recovered TB patients from subsequently contracting active TB.
