Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection
Abstract Background Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determin...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-06-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-025-03478-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849334554775519232 |
|---|---|
| author | Satoshi Suyama Sally Boxall Benjamin Grace Andrea Fořtová Martina Pychova Lenka Krbkova Rupasri Mandal David Wishart Diane E. Griffin Daniel Růžek Niluka Goonawardane |
| author_facet | Satoshi Suyama Sally Boxall Benjamin Grace Andrea Fořtová Martina Pychova Lenka Krbkova Rupasri Mandal David Wishart Diane E. Griffin Daniel Růžek Niluka Goonawardane |
| author_sort | Satoshi Suyama |
| collection | DOAJ |
| description | Abstract Background Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes. Methods CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay. Results Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection. Conclusions Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-depth studies of TBEV-induced neuropathogenesis, in which the depletion of identified metabolites limits virus infection. Collectively, this reveals new biomarkers that can differentiate and predict TBEV-associated neurological disease. Additionally, we have identified novel therapeutic targets with the potential to significantly improve patient outcomes and deepen our understanding of TBEV pathogenesis. |
| format | Article |
| id | doaj-art-9410060433974bd5b84f72cbcaab2c90 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-9410060433974bd5b84f72cbcaab2c902025-08-20T03:45:32ZengBMCJournal of Neuroinflammation1742-20942025-06-0122111910.1186/s12974-025-03478-4Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infectionSatoshi Suyama0Sally Boxall1Benjamin Grace2Andrea Fořtová3Martina Pychova4Lenka Krbkova5Rupasri Mandal6David Wishart7Diane E. Griffin8Daniel Růžek9Niluka Goonawardane10School of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of LeedsSchool of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of LeedsQueens’ College, University of CambridgeInstitute of Experimental Biology, Faculty of Science, Masaryk UniversityDepartment of Infectious Diseases, Faculty of Medicine, University Hospital Brno, Masaryk UniversityDepartment of Children’s Infectious Disease, Faculty of Medicine and University Hospital, Masaryk UniversityDepartment of Biological Sciences and Computing Science, University of AlbertaDepartment of Biological Sciences and Computing Science, University of AlbertaW. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public HealthInstitute of Experimental Biology, Faculty of Science, Masaryk UniversitySchool of Molecular and Cellular Biology, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of LeedsAbstract Background Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes. Methods CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay. Results Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection. Conclusions Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-depth studies of TBEV-induced neuropathogenesis, in which the depletion of identified metabolites limits virus infection. Collectively, this reveals new biomarkers that can differentiate and predict TBEV-associated neurological disease. Additionally, we have identified novel therapeutic targets with the potential to significantly improve patient outcomes and deepen our understanding of TBEV pathogenesis.https://doi.org/10.1186/s12974-025-03478-4Tick-borne encephalitis virusCerebrospinal fluidHuman motor neuronsMetabolomicsPro-inflammatory cytokinesChemokines |
| spellingShingle | Satoshi Suyama Sally Boxall Benjamin Grace Andrea Fořtová Martina Pychova Lenka Krbkova Rupasri Mandal David Wishart Diane E. Griffin Daniel Růžek Niluka Goonawardane Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection Journal of Neuroinflammation Tick-borne encephalitis virus Cerebrospinal fluid Human motor neurons Metabolomics Pro-inflammatory cytokines Chemokines |
| title | Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection |
| title_full | Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection |
| title_fullStr | Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection |
| title_full_unstemmed | Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection |
| title_short | Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection |
| title_sort | changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick borne encephalitis virus infection |
| topic | Tick-borne encephalitis virus Cerebrospinal fluid Human motor neurons Metabolomics Pro-inflammatory cytokines Chemokines |
| url | https://doi.org/10.1186/s12974-025-03478-4 |
| work_keys_str_mv | AT satoshisuyama changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT sallyboxall changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT benjamingrace changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT andreafortova changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT martinapychova changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT lenkakrbkova changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT rupasrimandal changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT davidwishart changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT dianeegriffin changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT danielruzek changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection AT nilukagoonawardane changesinmetaboliteprofilesinthecerebrospinalfluidandinhumanneuronalcellsupontickborneencephalitisvirusinfection |