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

Autor:	Ardiansyah E; Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia.; Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands., Pacheco JA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nhat LTH; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Dian S; Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia.; Department of Neurology, Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia., Vinh DN; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Hai HT; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Bullock K; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Alisjahbana B; Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia.; Department of Internal Medicine, Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia., Netea MG; Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands., Estiasari R; Department of Neurology, Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia., Tram TTB; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam., Donovan J; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; London School of Hygiene and Tropical Medicine, Keppel St, London, United Kingdom., Heemskerk D; Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centre, Amsterdam, the Netherlands., Chau TTH; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Hospital for Tropical Diseases, District 5, Ho Chi Minh City, Vietnam., Bang ND; Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, District 5, Ho Chi Minh City, Vietnam., Ganiem AR; Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia.; Department of Neurology, Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia., Ruslami R; Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia.; Department of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia., Koeken VA; Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands.; Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany., Hamers RL; Oxford University Clinical Research Unit Indonesia, Faculty of Medicine Universitas Indonesia., Imran D; Department of Neurology, Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia., Maharani K; Department of Neurology, Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia., Kumar V; Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands., Clish CB; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., van Crevel R; Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands., Thwaites G; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., van Laarhoven A; Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands., Thuong NTT; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Jan 09. Date of Electronic Publication: 2023 Jan 09.
DOI:	10.1101/2023.01.08.23284316
Abstrakt:	Background: Cellular 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. Methods: We 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. Results: CSF 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. Conclusion: TBM 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. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).
Databáze:	MEDLINE
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