Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study

Laarhoven, Arjan van; Dian, Sofiati; Aguirre-Gamboa, Raúl; Ávila-Pacheco, Julián; Ricaño-Ponce, Isis; Ruesen, Carolien; Annisa, Jessi; Koeken, Valerie A C M; Chaidir, Lidya; Li, Yang; Achmad, Tri Hanggono; Joosten, Leo A. B.; Notebaart, Richard A.; Ruslami, Rovina; Netea, Mihai G.; Verbeek, Marcel M.; Alisjahbana, Bachti; Kumar, Vinod; Clish, Clary B.; Ganiem, Ahmad Rizal; Crevel, Reinout van

doi:10.1016/s1473-3099(18)30053-7

Cited by 83 publications

(80 citation statements)

References 28 publications

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“…The prognostic potential of these genetic correlates was demonstrated in a validation cohort. These data suggest that tryptophan metabolism may play an important role in TBM outcome, and that further investigation into this metabolic pathway is warranted …”

Section: Pathogenic and Pathophysiologic Mechanisms Within The Brain mentioning

confidence: 86%

The pathogenesis of tuberculous meningitis

Davis

Rohlwink

Proust

et al. 2019

Journal of Leukocyte Biology

139

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Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested. K E Y W O R D S mycobacterial, endothelial cells, granulocytes, microglia cells, monocytes/macrophages, myeloid cells, neutrophils, T Lymphocytes, Th17 cells at the site of infection activates macrophages and DCs to produce cytokines and antimicrobial factors that contribute to containment of the TB bacillus. 2 This inflammatory process results in the formation of a granuloma, which encapsulates the infected cells and retards the replication of TB bacilli and can lead to latent infection. However, in

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Section: Pathogenic and Pathophysiologic Mechanisms Within The Brain mentioning

confidence: 86%

The pathogenesis of tuberculous meningitis

Davis

Rohlwink

Proust

et al. 2019

Journal of Leukocyte Biology

139

View full text Add to dashboard Cite

show abstract

“…Furthermore, IDO-expressing DCs are essential for maintaining granulomas, which contain Listeria monocytogenes and enable mycobacterial survival ( 99 ). More recently, cerebral tryptophan metabolism has also been shown to be important for the outcome of tuberculous meningitis, where low cerebrospinal fluid tryptophan concentrations strongly predicted patient survival ( 100 ). Hence, modulating L-tryptophan metabolism could be used as a potential HDT strategy.…”

Section: Metabolic Alterations Within Immune Cells During Mmentioning

confidence: 99%

Modulating Iron for Metabolic Support of TB Host Defense

et al. 2018

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Tuberculosis (TB) is the world's biggest infectious disease killer. The increasing prevalence of multidrug-resistant and extensively drug-resistant TB demonstrates that current treatments are inadequate and there is an urgent need for novel therapies. Research is now focused on the development of host-directed therapies (HDTs) which can be used in combination with existing antimicrobials, with a special focus on promoting host defense. Immunometabolic reprogramming is integral to TB host defense, therefore, understanding and supporting the immunometabolic pathways that are altered after infection will be important for the development of new HDTs. Moreover, TB pathophysiology is interconnected with iron metabolism. Iron is essential for the survival of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB disease. Mtb struggles to replicate and persist in low iron environments. Iron chelation has therefore been suggested as a HDT. In addition to its direct effects on iron availability, iron chelators modulate immunometabolism through the stabilization of HIF1α. This review examines immunometabolism in the context of Mtb and its links to iron metabolism. We suggest that iron chelation, and subsequent stabilization of HIF1α, will have multifaceted effects on immunometabolic function and holds potential to be utilized as a HDT to boost the host immune response to Mtb infection.

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“…We failed to identify pathways that allow discrimination Borrelia -stimulated PBMCs from LPS and MTB-stimulated PBMCs. Activation of tryptophan metabolism was previously reported in human marcophages in vitro upon MTB stimulation (Blumenthal et al, 2012 ), and a recent study (van Laarhoven et al, 2018 ) has identified a crucial role of tryptophan metabolism for the pathophysiology of tuberculous meningitis. In addition, enhancement of tryptophan catabolism is an IFN (interferon) γ-induced immune response in many different host cell types, and has been postulated to reduce the supply of tryptophan to bacterial pathogens (Moffett and Namboodiri, 2003 ; O'Neill et al, 2016 ).…”

Section: Discussionmentioning

confidence: 69%

Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents

et al. 2018

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Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol) that might serve as biomarkers discriminating Candida-stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense.

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Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study

Cited by 83 publications

References 28 publications

The pathogenesis of tuberculous meningitis

The pathogenesis of tuberculous meningitis

Modulating Iron for Metabolic Support of TB Host Defense

Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents

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