Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.
Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.
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色氨酸代谢决定结核性脑膜炎的结果：靶向代谢组学分析。
DOI：
10.1101/2023.01.08.23284316
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Chau,T
中科院分区：
文献类型：
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作者：
Ardiansyah,Edwin;Pacheco,JulianAvila;Nhat,LeThanhHoang;Dian,Sofiati;Vinh,DaoNguyen;Hai,HoangThanh;Bullock,Kevin;Alisjahbana,Bachti;Netea,MihaiG;Estiasari,Riwanti;Tram,TrinhThiBich;Donovan,Joseph;Heemskerk,Dorothee;Chau,T
背景：细胞代谢对宿主抵抗病原体的免疫功能至关重要，代谢组学分析有助于了解结核病的免疫病理学特征。我们进行了有针对性的代谢组学分析，在一个大的队列结核性脑膜炎（TBM），结核病的最严重的表现，重点是色氨酸metabolic.Methods：我们研究了1069印尼和越南成年人与TBM（26.6%HIV阳性），54非感染性对照，50与细菌性脑膜炎，60与隐球菌性脑膜炎。使用靶向液相色谱-质谱法测定脑脊液（CSF）和血浆中的色氨酸和下游代谢物。个别代谢物水平与生存，临床参数，CSF细菌负荷和92 CSF inflammatory proteins.Results：CSF色氨酸与60天死亡率从TBM（危害比[HR]= 1.16，95%置信区间[CI]= 1.10-1.24，在CSF色氨酸每增加一倍）在HIV阴性和阳性patients。CSF色氨酸浓度与CSF细菌负荷和CSF炎症无关，但与CSF干扰素-γ浓度呈负相关。与色氨酸不同，下游犬尿氨酸代谢物的相互关联簇的CSF浓度不能预测死亡率。然而，这些CSF犬尿氨酸代谢物确实与CSF炎症和血液-CSF渗漏标志物相关，血浆犬尿氨酸预测死亡（HR 1.54，95% CI= 1.22-1.93）。这些研究结果大多是具体的TBM，虽然高CSF色氨酸也与死亡率隐球菌meningitis.Conclusions：TBM患者高基线CSF色氨酸或高全身（血浆）犬尿氨酸的死亡风险增加。这些发现可能揭示宿主导向治疗的新靶点。
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 TBM (hazard ratio [HR]= 1.16, 95% confidence interval [CI]= 1.10–1.24, for each doubling in CSF tryptophan) both in HIV-negative and-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.Conclusions:TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy.