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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Virol
2017 ; 91
(14
): ä Nephropedia Template TP
gab.com Text
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English Wikipedia
Central Nervous System Infection with Borna Disease Virus Causes Kynurenine
Pathway Dysregulation and Neurotoxic Quinolinic Acid Production
#MMPMID28446679
Formisano S
; Hornig M
; Yaddanapudi K
; Vasishtha M
; Parsons LH
; Briese T
; Lipkin WI
; Williams BL
J Virol
2017[Jul]; 91
(14
): ä PMID28446679
show ga
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.