Identification of differentially expressed genes in brains of newborn Borna disease virus-infected rats in the absence of inflammation

The neurotropic virus Borna disease virus (BDV) persists in the central nervous systems of a wide variety of vertebrates and causes behavioral disorders. BDV represents an intriguing example of a virus whose persistence in neurons leads to altered brain function in the absence of overt cytolysis and inflammation. The bases of BDV-induced behavioral impairment remain largely unknown. To better characterize the neuronal response to BDV infection, we compared the proteomes of primary cultures of cortical neurons with and without BDV infection. We used two-dimensional liquid chromatography fractionation, followed by protein identification by nanoliquid chromatography-tandem mass spectrometry. This analysis revealed distinct changes in proteins implicated in neurotransmission, neurogenesis, cytoskeleton dynamics, and the regulation of gene expression and chromatin remodeling. We also demonstrated the selective interference of BDV with processes related to the adaptative response of neurons, i.e., defects in proteins regulating synaptic function, global rigidification of the cytoskeleton network, and altered expression of transcriptional and translational repressors. Thus, this work provides a global view of the neuronal changes induced by BDV infection together with new clues to understand the mechanisms underlying the selective interference with neuronal plasticity and remodeling that characterizes BDV persistence.The analysis of the response of a host cell to a pathogenic microorganism represents a daunting task, as it often results in complex and numerous changes in gene expression (37). Generally, these changes strongly depend on the nature of the pathogen interaction with its host. In the case of the central nervous system (CNS), the deleterious consequences of viral infection are often due to the cytopathic nature of viral replication (25, 38), or, alternatively, they can result from the immune response to the virus (31). However, some viruses can also persist in the CNS and cause diseases without an overt cytopathic effect or inflammation (1). These viral models provide a unique opportunity to unravel the molecular mechanisms underlying virus-induced neuronal dysfunction. A better understanding of the pathological consequences of viral persistence in the CNS may help to shed light on the pathogenesis of many neurological diseases of unclear etiology where viruses are thought to play a role (34, 47).Infection with Borna disease virus (BDV) represents an ideal paradigm for the investigation of the neuronal consequences due to the persistence of a noncytolytic virus. BDV is an enveloped virus with a nonsegmented, negative-strand RNA genome (13, 44). BDV infects a wide variety of mammals (35), possibly including humans (6, 29). Infected hosts develop a large spectrum of neurological disorders, ranging from immune-mediated diseases to behavioral alterations without inflammation (35, 41), reminiscent of symptoms observed in certain human neuropsychiatric diseases (28). These neurobehavioral manifestations reflect th...

Section: Discussioncontrasting

confidence: 45%

Proteomic Analysis Reveals Selective Impediment of Neuronal Remodeling upon Borna Disease Virus Infection

Suberbielle

Stella

Pont

et al. 2008

“…Untreated control hippocampal cultures showed a typical cellular arrangement of granule cells and a normal mossy fiber projection in the CA3 region of the hippocampus after 28 days of culturing as determined by immunofluorescence analysis using an antibody against calbindin, a marker protein for differentiated granule cells (Fig. 1A, top left) (19). This antibody also recognizes calbindin-positive interneurons in hippocampal subfields.…”

Section: Infection Of Hippocampal Slice Cultures From Newborn Rats Wimentioning

confidence: 89%

“…Virus stocks from Oligo cells persistently infected with BDV strain He/80 were prepared as previously described (8) and subsequently dialyzed in PBS for 48 h. Determination of viral titers was carried out on Vero cells as previously described (8). Rat brain-derived virus stock strain RW98, (19) was obtained from Christian Sauder (Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Md. ).…”

Section: Methodsmentioning

confidence: 99%

Borna Disease Virus Replication in Organotypic Hippocampal Slice Cultures from Rats Results in Selective Damage of Dentate Granule Cells

Mayer

Fischer

Schneider

et al. 2005

In the hippocampus of Borna disease virus (BDV)-infected newborn rats, dentate granule cells undergo progressive cell death. BDV is noncytolytic, and the pathogenesis of this neurodevelopmental damage in the absence of immunopathology remains unclear. A suitable model system to study early events of the pathology is lacking. We show here that organotypic hippocampal slice cultures from newborn rat pups are a suitable ex vivo model to examine BDV neuropathogenesis. After challenging hippocampal slice cultures with BDV, we observed a progressive loss of calbindin-positive granule cells 21 to 28 days postinfection. This loss was accompanied by reduced numbers of mossy fiber boutons when compared to mock-infected cultures. Similarly, the density of dentate granule cell axons, the mossy fiber axons, appeared to be substantially reduced. In contrast, hilar mossy cells and pyramidal neurons survived, although BDV was detectable in these cells. Despite infection of dentate granule cells 2 weeks postinfection, the axonal projections of these cells and the synaptic connectivity patterns were comparable to those in mock-infected cultures, suggesting that BDVinduced damage of granule cells is a postmaturation event that starts after mossy fiber synapses are formed. In summary, we find that BDV infection of rat organotypic hippocampal slice cultures results in selective neuronal damage similar to that observed with infected newborn rats and is therefore a suitable model to study BDV-induced pathology in the hippocampus.Borna disease virus (BDV) is a nonsegmented negativestrand RNA virus that persistently infects the central nervous system (CNS) and causes behavioral abnormalities in a broad range of vertebrates (17,25). Depending on the age and immune status of the host, BDV infection may present as immune-mediated neurological disease with fatal outcome (Borna disease) or subtle behavioral alterations without overt inflammation (17,25). BDV infection is potentially linked to psychiatric diseases, as BDV-specific antibodies were identified in sera of psychiatric patients with higher prevalence than in sera from control cohorts (24). However, attempts to confirm human BDV by nonserological methods, including detection of viral nucleic acid by nested reverse transcription-PCR or virus isolation, revealed inconsistent results (35); this issue is therefore still controversial.Rats are the best-characterized animal models for studying BDV-induced pathogenesis. Depending on the age of the rat at the time of infection, the spectrum of BDV-caused diseases ranges from a progressive immune-mediated meningoencephalitis to behavioral abnormalities (17,25,26). In adult immunocompetent rats, BDV infection causes a biphasic disease characterized by a classical immune-mediated CNS disorder. This disease is associated with massive neuronal destruction and behavioral disturbances, the near-resolution of inflammatory infiltrates, virus persistence, and signs of chronic neurological disease. In contrast to infected adult rats, infection of neon...

“…IFN-␣/␤ was also found in BDV-infected cell cultures and was shown to inhibit BDV replication (20,50,56). In addition, a variety of chemokine-encoding mRNAs are upregulated in BDV-infected brain tissue (9,25,45).…”

mentioning

confidence: 96%

Constitutive Activation of the Transcription Factor NF-κB Results in Impaired Borna Disease Virus Replication

Bourteele

Oesterle

Pleschka

et al. 2005