Persistent human Borna disease virus infection modifies the acetylome of human oligodendroglia cells towards higher energy and transporter levels

Liu, Xia; Liu, Siwen; Bode, Liv; Liu, Chengyu; Zhang, Liang; Wang, Xiao; Li, Dan; Yang, Lei; Peng, Xiaojun; Cheng, Zhongyi; Xie, Peng

doi:10.1016/j.virol.2015.06.024

Cited by 13 publications

(15 citation statements)

References 55 publications

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“…While we have not examined levels of 3-HK, this metabolite could further contribute to neural damage through its ability to generate hydroxyl radicals if it is also elevated by BDV infection. Altered expression of kynurenine enzymes and metabolites could also be linked to previous findings demonstrating that the metabolism of several amino acids, including tryptophan, were altered following BDV infection in oligodendroglia (64). …”

Section: Discussionsupporting

confidence: 62%

Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production

Formisano

Hornig

Yaddanapudi

et al. 2017

J Virol

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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.

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Section: Discussionsupporting

confidence: 62%

Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production

Formisano

Hornig

Yaddanapudi

et al. 2017

J Virol

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“…A recent publication could demonstrate that this human BDV strain, Hu-H1, also impacts important post-translational modifications like acetylation upon infection. The acetylome of infected OL cells was manipulated towards higher energy and transporter levels [ 25 ]. Most notably, human strain BDV Hu-H1 and laboratory strain (Str.…”

Section: Introductionmentioning

confidence: 99%

GC–MS-Based Metabonomic Profiling Displayed Differing Effects of Borna Disease Virus Natural Strain Hu-H1 and Laboratory Strain V Infection in Rat Cortical Neurons

Liu

Bode

Zhang

et al. 2015

IJMS

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Borna disease virus (BDV) persists in the central nervous systems of a wide variety of vertebrates and causes behavioral disorders. Previous studies have revealed that metabolic perturbations are associated with BDV infection. However, the pathophysiological effects of different viral strains remain largely unknown. Rat cortical neurons infected with human strain BDV Hu-H1, laboratory BDV Strain V, and non-infected control (CON) cells were cultured in vitro. At day 12 post-infection, a gas chromatography coupled with mass spectrometry (GC–MS) metabonomic approach was used to differentiate the metabonomic profiles of 35 independent intracellular samples from Hu-H1-infected cells (n = 12), Strain V-infected cells (n = 12), and CON cells (n = 11). Partial least squares discriminant analysis (PLS-DA) was performed to demonstrate discrimination between the three groups. Further statistical testing determined which individual metabolites displayed significant differences between groups. PLS-DA demonstrated that the whole metabolic pattern enabled statistical discrimination between groups. We identified 31 differential metabolites in the Hu-H1 and CON groups (21 decreased and 10 increased in Hu-H1 relative to CON), 35 differential metabolites in the Strain V and CON groups (30 decreased and 5 increased in Strain V relative to CON), and 21 differential metabolites in the Hu-H1 and Strain V groups (8 decreased and 13 increased in Hu-H1 relative to Strain V). Comparative metabonomic profiling revealed divergent perturbations in key energy and amino acid metabolites between natural strain Hu-H1 and laboratory Strain V of BDV. The two BDV strains differentially alter metabolic pathways of rat cortical neurons in vitro. Their systematic classification provides a valuable template for improved BDV strain definition in future studies.

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“…In contrast, decreased amount of acetylated CypA was found in samples of amyotrophic lateral sclerosis patients than in samples of healthy humans . Moreover, lysine acetylation seems to regulate the functions of CypA in immunity and viral infections .…”

Section: Resultsmentioning

confidence: 74%

Identification of low abundance cyclophilins in human plasma

et al. 2016

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Cylophilins (Cyps) belong to the ubiquitously distributed enzyme class of peptidyl prolyl cis/trans isomerases (EC5.2.1.8), which are foldases capable of accelerating slow steps in the refolding of denatured proteins. At least 20 different Cyp isoenzymes are broadly distributed among all organs and cellular compartments in humans. Extracellularly localized Cyps came into the scientific focus recently because of their involvement in the control of inflammatory diseases, as well as viral and bacterial infections. However, detailed insights into Cyp functions are often hampered by the lack of sensitive detection methods. We present an improved method for affinity purification and detection of Cyp in biotic samples in this manuscript. The procedure takes advantage of two novel cyclosporine A derivatives. Derivative 1 was used to capture Cyps from the sample while derivative 2 was applied for selective release from the affinity matrix. Using this approach, eight different Cyp (CypA, CypB, CypC, Cyp40 (PPID), CypE, CypD (PPIF), CypH, and CypL1) were unambiguously detected in healthy human blood plasma. Moreover, extracellular CypA was found to be partially modified by N acetylation on residues Lys44, Lys133, Lys155, as well as N acetylation at the N-terminal Val residue. N acetylation of Ser2 residue was also found for Cyp40.

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Persistent human Borna disease virus infection modifies the acetylome of human oligodendroglia cells towards higher energy and transporter levels

Abstract: Upon BDV persistence the OL acetylome is manipulated towards higher energy and transporter levels necessary for shuttling BDV proteins to and from nuclear replication sites.

Cited by 13 publications

References 55 publications

Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production

Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production

GC–MS-Based Metabonomic Profiling Displayed Differing Effects of Borna Disease Virus Natural Strain Hu-H1 and Laboratory Strain V Infection in Rat Cortical Neurons

Identification of low abundance cyclophilins in human plasma

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