Tuberculosis patients could soon receive common drugs like aspirin or vitamin D alongside their antibiotics to help their own immune systems fight the infection more effectively. Current TB treatment relies solely on antibiotics, but the immune system’s own response can cause collateral damage—inflammation that destroys lung tissue and makes it harder to clear the bacteria. Some patients, particularly those with HIV, suffer from a dangerous overreaction when their immune system rebounds. Others develop cavities in their lungs that harbour persistent bacteria. This project tests whether adding an anti-inflammatory or immune-boosting drug can short-circuit that damage. The researchers will first screen potential therapies using human cells in the lab, bypassing the usual animal testing step. They will then run three small clinical trials: one testing vitamin D to prevent immune reconstitution syndrome in HIV-TB patients, one testing aspirin to speed healing in people with advanced cavitating TB, and one testing vitamin D to boost immunity in people recently exposed to TB. Each trial will combine detailed molecular profiling with PET-CT scans to track what happens inside the lungs. If any of these repurposed drugs prove safe and effective, they could be added to standard TB treatment at low cost, shortening recovery times and reducing permanent lung damage. The results will also guide the design of a larger Phase III trial.
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We hypothesise that adjunctive immunomodulatory host-directed therapies can improve outcome in tuberculosis by: 1. Hastening resolution of a hyperinflammatory immune response that induces tissue damage and antagonises antibiotic therapy. 2. Boosting endogenous host antimicrobial defence. Adjunctive anti-inflammatory or antimicrobial (referred to as host-directed) therapy proposes reducing tissue damage and time to bacillary clearance via the modulation of host defence mechanisms. We will b reak the pre-clinical paradigm of prior animal testing via in vitro screening of agents. Using biomarkers of the in vitro immune response we will investigate pathways amenable to host-directed pharmacological intervention in two tissue culture models, using cells from three distinct phenotypes of tuberculosis-infected persons. This will inform the subsequent design of three proof-of-concept phase IIA clinical studies that will couple ex vivo transcriptomic, flow cytometric, and multianalyte prof iling to in vivo combined positron emission and computed axial tomography imaging. In turn findings from the proof-of-concept studies will feedback into the design of further in vitro analyses and forward into the design of a Phase III trial to be funded separately. The specific aims are to 1. Establish and employ in vitro methods to evaluate the potential efficacy of host-directed therapies against tuberculosis 2. To perform phase IIA proof-of-concept clinical studies evaluating the safety and potential efficacy of a.) vitamin D anti-inflammatory therapy to prevent HIV-tuberculosis associated immune reconstitution inflammatory syndrome b.) Aspirin anti-inflammatory therapy to hasten resolution of advanced cavitating pulmonary tuberculosis c.) vitamin D to enhance immunity in recent tuberculosis contacts
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