Dataset Information

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway.

ABSTRACT:

Objective

To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE).

Methods

This study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non-inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA.

Results

Kyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non-inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups.

Interpretation

The results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.

SUBMITTER: Luo Y

PROVIDER: S-EPMC8670317 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Central nervous system infection of neonatal and adult rats with Borna disease virus (BDV) results in neuronal destruction and behavioral abnormalities with differential immune-mediated involvement. Neuroactive metabolites generated from the kynurenine pathway of tryptophan degradation have been implicated in several human neurodegenerative disorders. Here, we report that brain expression of key enzymes in the kynurenine pathway are significantly, but differentially, altered in neonatal and adult rats with BDV infection. Gene expression analysis of rat brains following neonatal infection showed increased expression of kynurenine amino transferase II (KATII) and kynurenine-3-monooxygenase (KMO) enzymes. Additionally, indoleamine 2,3-dioxygenase (IDO) expression was only modestly increased in a brain region- and time-dependent manner in neonatally infected rats; however, its expression was highly increased in adult infected rats. The most dramatic impact on gene expression was seen for KMO, whose activity promotes the production of neurotoxic quinolinic acid. KMO expression was persistently elevated in brain regions of both newborn and adult BDV-infected rats, with increases reaching up to 86-fold. KMO protein levels were increased in neonatally infected rats and colocalized with neurons, the primary target cells of BDV infection. Furthermore, quinolinic acid was elevated in neonatally infected rat brains. We further demonstrate increased expression of KATII and KMO, but not IDO, in vitro in BDV-infected C6 astroglioma cells. Our results suggest that BDV directly impacts the kynurenine pathway, an effect that may be exacerbated by inflammatory responses in immunocompetent hosts. Thus, experimental models of BDV infection may provide new tools for discriminating virus-mediated from immune-mediated impacts on the kynurenine pathway and their relative contribution to neurodegeneration.IMPORTANCE BDV causes persistent, noncytopathic infection in vitro yet still elicits widespread neurodegeneration of infected neurons in both immunoincompetent and immunocompetent hosts. Here, we show that BDV infection induces expression of key enzymes of the kynurenine pathway in brains of newborn and adult infected rats and cultured astroglioma cells, shunting tryptophan degradation toward the production of neurotoxic quinolinic acid. Thus, our findings newly implicate this metabolic pathway in BDV-induced neurodegeneration. Given the importance of the kynurenine pathway in a wide range of human infections and neurodegenerative and neuropsychiatric disorders, animal models of BDV infection may serve as important tools for contrasting direct viral and indirect antiviral immune-mediated impacts on kynurenine pathway dysregulation and the ensuing neurodevelopmental and neuropathological consequences.