Improving host-directed therapy for tuberculous meningitis by linking clinical and multi-omics data

There is a clear need to improve host-directed therapy for tuberculous meningitis (TBM), the most severe and deadly manifestation of tuberculosis. Corticosteroids represent the only host-directed therapy of proven benefit in TBM, yet their effect is modest, the mechanism by which they reduce mortality is unknown, and there is evidence for heterogeneity in their effect. Novel therapeutic approaches are therefore urgently needed. Cellular metabolism is critical for the function of immune cells; through unbiased metabolomics we recently found that high concentrations of cerebrospinal fluid (CSF) tryptophan are associated with increased mortality in Indonesian TBM patients, and that CSF tryptophan concentrations are under strong genetic regulation. Many questions remain. How exactly is tryptophan metabolism altered during TBM? How does it correlate with inflammation, immunopathology, and response to corticostemids? How is tryptophan metabolism genetically regulated? What is the effect of HIV co-infection on tryptophan metabolism before and during TBM treatment? The ULTIMATE project addresses these questions by integrating data and specimens from large patient studies and clinical trials evaluating the effects of corticosteroids in Vietnam and Indonesia. Through its powerful and unbiased approach, ULTIMATE aims to identify which TBM patients benefit from corticosteroids and if novel therapeutic targets, such as the tryptophan pathway, could be targeted.

Automated summary

There is a clear need to improve host-directed therapy for tuberculous meningitis (TBM), as the current therapy options are limited. The ULTIMATE project aims to address unanswered questions about tryptophan metabolism during TBM and identify novel therapeutic targets for TBM patients. Through integrating data from large patient studies and clinical trials, ULTIMATE seeks to determine which TBM patients benefit from corticosteroids and explore the potential of targeting the tryptophan pathway for treatment.