Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis

Abstract

BackgroundCellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism.MethodsWe studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins.ResultsCSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis.ConclusionTBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy.FundingThis study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks

“…Indeed, increased tryptophan catabolism in the CNS of persons with TBM has been associated with increased survival. (13,14) We observe significantly elevated Th1 (IL-2, IFNg), Th2 (IL-4) and Th17 (IL-17, IL-6, TNFa) effector cytokines in the CSF of persons with TBM, (31) and these cytokines were correlated with CSF concentrations of kynurenine and kynurenic acid. This indicates tryptophan catabolism represents a counter-regulatory process to limit T-cell-mediated inflammation.…”

“…While increased CSF concentrations of proinflammatory cytokines IL-1b, TNFa, IL-6, and IFNg are associated with greater disease severity at diagnosis, studies to date have yielded conflicting results about their impact on long-term morbidity and mortality. (8,10,11) Some of this variability may be due to differences in host genetic (12) and metabolic factors (13,14), which have generally gone unmeasured in studies of TBM. Indeed, differences in tryptophan and eicosanoid metabolism are the only host response pathways shown to impact TBM mortality.…”

“…Indeed, differences in tryptophan and eicosanoid metabolism are the only host response pathways shown to impact TBM mortality. (8,(12)(13)(14) However, the relationship TB meningitis immunometabolic networks between metabolic and cytokine signaling in the CNS of TBM patients and the trajectory of these signaling networks during treatment remain largely unexplored.…”

Dynamic PET Reveals Compartmentalized Brain and Lung Tissue Antibiotic Exposures

“…Speci cally, pyrazinamide-containing regimens had signi cantly lower intracerebral in ammation. High CSF tryptophan levels are associated with increased mortality in patients with TB meningitis 42 , and CSF and plasma tryptophan levels were lower in mice treated with the optimized regimens. Similarly, elevated levels of brain injury markers [GFAP, NEFL (or N ), Tau and S100B] in the CSF or plasma, are associated with poor outcomes in patients with brain damage 43 , and in TB meningitis 44 , and brain injury marker levels in CSF and plasma were lower in mice treated with the optimized regimens.…”

Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis

“…Immune responses in TBM are thought to be compartmentalized within the central nervous system. Studies have shown that immune cell counts, cytokine concentrations, metabolites and transcriptional responses differ between the peripheral blood and the cerebrospinal fluid (CSF) 10,12,13 . In adults with TBM, leukocyte activation is higher in the CSF than in peripheral blood, although a marked myeloid response in peripheral blood has been reported 10 .…”