PRECISE-TBM

Childhood Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB), mostly affecting children. Diagnosis of TBM in children is challenging, necessitating up to six visits to hospitals. Furthermore, 50% of people who are diagnosed with TBM die or suffer life-long neurological problems. We previously identified, patented, and validated a 3-protein cerebrospinal fluid (CSF) biomarker signature, including IFN-γ, for the diagnosis of childhood TBM. We have developed a prototype point-of-care (PoC) lateral flow test based on this biosignature, in collaboration with LifeSADX, an industrial partner based in South Africa. We also developed a variant of the CSF-based test, based on the biosensor technology and have identified blood-based (BB) biomarkers which require refinement and subsequent development into a TBM PoC test. The potential alterations of IFN-γ detection or function due to autoantibodies or genetic mutations in these patients is currently unknown. In this project, we aim to: 1) Gather evidence on the performances of the two newly developed CSF-based PoC tests at hospitals situated in South Africa, Zambia, and Zimbabwe 2) Refine our previously identified BB-biosignature in stored multi-country specimens, and incorporate the refined biomarkers into a new TBM prototype test, using biosensor technology 3) Prospectively evaluate the blood-based prototype test alongside the CSF-based tests 4) Test both immunologically and genetically, defects in IFN-γ immunity, a key biomarker on our CSF-based tests, in CSF and serum samples, and ascertain the relevance of such defects to possible disease development, and their influence on PoC test results The project will bring together a multi-disciplinary team with different but complementary expertise including immunologists, human geneticists, neurologists, social scientists, and an industrial partner based in South Africa, and has potential to significantly influence the management of childhood TBM worldwide.