Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis
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 death. 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).
Data availability
The data generated or analysed during this study are included in the supporting file.
Article and author information
Author details
Funding
National Institutes of Health (R01AI145781)
- Edwin Ardiansyah
- Julian Avila Pacheco
- Nhat Thanh Hoang Le
- Sofiati Dian
- Dao Nguyen Vinh
- Hoang Thanh Hai
- Kevin Bullock
- Bachti Alisjahbana
- Mihai G Netea
- Riwanti Estiasari
- Trinh Thi Bich Tram
- Joseph Donovan
- Dorothee Heemskerk
- Tran Thi Hong Chau
- Nguyen Duc Bang
- Ahmad Rizal Ganiem
- Valerie ACM Koeken
- Raph L Hamers
- Darma Imran
- Kartika Maharani
- Vinod Kumar
- Clary B Clish
- Reinout van Crevel
- Guy E Thwaites
- Arjan van Laarhoven
- Nguyen TT Thuong
Wellcome Trust
- Nhat Thanh Hoang Le
- Dao Nguyen Vinh
- Hoang Thanh Hai
- Trinh Thi Bich Tram
- Joseph Donovan
- Dorothee Heemskerk
- Tran Thi Hong Chau
- Nguyen Duc Bang
- Guy E Thwaites
- Nguyen TT Thuong
Direktorat Jendral Pendidikan Tinggi, Indonesia (BPPLN)
- Sofiati Dian
Ministry of Research, Technology, and Higher Education, Indonesia (PKSLN)
- Sofiati Dian
- Rovina Ruslami
United States Agency for International Development (PEER Health)
- Rovina Ruslami
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Ethical approval was obtained from the Ethical Committee of Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia and from the Oxford Tropical Research Ethics Committee in the United Kingdom, the Institutional Review Boards of the Hospital for Tropical Diseases and Pham Ngoc Thach Hospital in Vietnam. Written (Vietnam) or oral (Indonesia) consent to be included in the study, for storage of surplus sample, and to obtain follow-up data was obtained from patients or close relatives of patients who were unconscious.
Copyright
© 2023, Ardiansyah et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,135
- views
-
- 181
- downloads
-
- 14
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.