色氨酸代谢决定结核性脑膜炎的预后：一项靶向代谢组学分析

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

作者信息

Ardiansyah Edwin, Pacheco Julian Avila, Nhat Le Thanh Hoang, Dian Sofiati, Vinh Dao Nguyen, Hai Hoang Thanh, Bullock Kevin, Alisjahbana Bachti, Netea Mihai G, Estiasari Riwanti, Tram Trinh Thi Bich, Donovan Joseph, Heemskerk Dorothee, Chau Tran Thi Hong, Bang Nguyen Duc, Ganiem Ahmad Rizal, Ruslami Rovina, Koeken Valerie Acm, Hamers Raph L, Imran Darma, Maharani Kartika, Kumar Vinod, Clish Clary B, van Crevel Reinout, Thwaites Guy, van Laarhoven Arjan, Thuong Nguyen Thuy Thuong

机构信息

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.

出版信息

medRxiv. 2023 Jan 9:2023.01.08.23284316. doi: 10.1101/2023.01.08.23284316.

DOI:10.1101/2023.01.08.23284316

PMID:36711829

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9882445/

Abstract

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).

摘要

背景

细胞代谢对于宿主抵抗病原体的免疫功能至关重要，代谢组学分析可能有助于理解结核病的特征性免疫病理学。我们对一大群结核性脑膜炎（TBM）患者进行了靶向代谢组学分析，TBM是结核病最严重的表现形式，重点关注色氨酸代谢。

方法

我们研究了1069名印度尼西亚和越南的成年TBM患者（26.6%为HIV阳性）、54名非感染性对照、50名细菌性脑膜炎患者和60名隐球菌性脑膜炎患者。使用靶向液相色谱质谱法测量脑脊液（CSF）和血浆中的色氨酸及下游代谢产物。个体代谢产物水平与生存率、临床参数、CSF细菌载量和92种CSF炎症蛋白相关。

结果

在HIV阴性和HIV阳性患者中，CSF色氨酸均与结核性脑膜炎60天死亡率相关（HR = 1.16，95%CI = 1.10 - 1.24，CSF色氨酸每增加一倍）。CSF色氨酸浓度与CSF细菌载量和CSF炎症均无相关性，但与CSF干扰素-γ浓度呈负相关。与色氨酸不同，一组相互关联的下游犬尿氨酸代谢产物的CSF浓度不能预测死亡率。然而，这些CSF犬尿氨酸代谢产物与CSF炎症及血脑屏障渗漏标志物相关，血浆犬尿氨酸可预测死亡（HR 1.54，95%CI = 1.22 - 1.93）。这些发现大多对TBM具有特异性，尽管高CSF色氨酸也与隐球菌性脑膜炎死亡率相关。