INTERCEPT

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Project Summary/abstract Tuberculous meningitis (TBM) disproportionally affects small children, and immunopathology likely contributes to its high mortality and physical and cognitive morbidity. Recent unbiased cross-omics studies have identified biological pathways involved in the outcome of TBM in adults that could help development of more effective host- directed therapy for TBM, but it is unknown if similar or other pathways are implicated in childhood TBM. We previously identified high levels of cerebrospinal fluid (CSF) tryptophan, a nutrient for Mycobacterium tuberculosis, and genetic traits that predict CSF tryptophan concentrations as strong markers for mortality of TBM. By integrating large-scale clinical, metabolomics and genomics data we have strengthened these findings and identified additional metabolic pathways implicated in outcome of TBM in adult patients. Separately, we found that CSF levels of matrix metalloproteinases (MMP-10), as well as genetic traits associated with CSF MMP-10 levels, also predict mortality of adult TBM patients. This suggests that metalloproteinases may also be implicated in TBM outcome, possibly through blood-brain barrier dysfunction resulting in cerebral edema and influx of inflammatory cells. These findings raise the question if these biological pathways are also involved in the immunopathology and poor outcome of pediatric TBM. Lastly, we recently showed that adjunctive aspirin might reduce brain infarctions and death from TBM in adults. Therefore, we are conducting a separately funded phase 3 clinical trial of aspirin in children with TBM to determine if it reduces mortality and long-term disability. Therefore, based on our previous work we hypothesize that: specific metabolic pathways including tryptophan metabolism influence outcome of pediatric TBM, and that this is genetically regulated (Aim 1); metalloproteinases are implicated in the immunopathology and outcome of TBM (Aim 2); and integration of large-scale clinical and ‘omics’ data and comparison of pediatric and adult TBM patients can predict the therapeutic effect of aspirin, and identify novel targets for host-directed therapy of pediatric TBM (Aim 3). To test these hypotheses, we will combine unique access to some of the largest clinical studies in TBM globally with exceptional expertise in integration of multi-omics and deep-phenotyping data. Our strong preliminary data, access to two large bioarchives from adult TBM, an on-going randomized controlled trial in pediatric TBM, and expertise in integration of large-scale clinical and multi-layer ‘omics’ data promises to provide a step-change in understanding childhood TBM pathogenesis and discovery of new targets for future host-directed therapies.