Borna Disease Virus Multiplication in Mouse Organotypic Slice Cultures Is Site-Specifically Inhibited by Gamma Interferon but Not by Interleukin-12

Friedl, Gregor; Höfer, Markus; Auber, Bernd; Sauder, Christian; Hausmann, Jürgen; Staeheli, Peter; Pagenstecher, Axel

doi:10.1128/jvi.78.3.1212-1218.2004

Cited by 20 publications

(15 citation statements)

References 23 publications

(26 reference statements)

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“…For every condition total RNA of three independent transduction sets was isolated for each investigated culture passage and analyzed with a probe set described before [26]. To determine the expression of human c-Myc in transduced astrocytes by RPA a specific 236 bp long target sequences was used to generate a probe against c-myc (NM_002764.4; nucleotides 1404 to 1639) as described previously [22].…”

Section: Methodsmentioning

confidence: 99%

Akt and c-Myc Induce Stem-Cell Markers in Mature Primary p53−/− Astrocytes and Render These Cells Gliomagenic in the Brain of Immunocompetent Mice

2013

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Astrocytomas and their most malignant variant glioblastoma multiforme (GBM) represent the vast majority of primary brain tumors. Despite the current progress in neurosurgery, radiation therapy and chemotherapy, most astrocytomas remain fatal disorders. Although brain tumor biology is a matter of intense research, the cell-of-origin and the complete astrocytoma-inducing signaling pathway remain unknown. To further identify the mechanisms leading to gliomagenesis, we transduced primary astrocytes on a p53−/− background with c-Myc, constitutively active myr-Akt or both, myr-Akt and c-Myc. Transduced astrocytes showed oncogene-specific alterations of morphology, proliferation and differentiation. Following prolonged periods of cultivation, oncogene-transduced astrocytes expressed several stem-cell markers. Furthermore, astrocytes coexpressing c-Myc and Akt were tumorigenic when implanted into the brain of immunocompetent C57BL/6 mice. Our results reveal that the loss of p53 combined with oncogene overexpression in mature astrocytes simulates pivotal features of glioma pathogenesis, providing a good model for assessing the development of secondary glioblastomas.

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Section: Methodsmentioning

confidence: 99%

Akt and c-Myc Induce Stem-Cell Markers in Mature Primary p53−/− Astrocytes and Render These Cells Gliomagenic in the Brain of Immunocompetent Mice

2013

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“…2) [84]. This effect is reproduced in vitro in cerebellar slice cultures by IFN-γ but not by IL-12 [85]. In all, these studies show that IL-12 can drive an otherwise ineffective anti-viral T-cell response in the CNS and from which IFN-γ directly inhibits viral replication and/or spread.…”

Section: Interleukin-12 (Il-12) Stimulates Type I Cell-mediated Imentioning

confidence: 99%

Transgenic models for cytokine-induced neurological disease

Campbell

Höfer

Pagenstecher

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Considerable evidence supports the idea that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in a variety of neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. One approach to address this problem that has been used widely employs transgenic mice with CNS-targeted production of different cytokines. Transgenic production of cytokines in the CNS of mice allows not only for the investigation of complex cellular responses at a localized level in the intact brain, but also more closely recapitulates the expression of these mediators as found in disease states. As discussed in this review, the findings show that these transgenic animals exhibit wide-ranging structural and functional deficits that are linked to the development of distinct neuroinflammatory responses which are relatively specific for each cytokine. These cytokine-induced alterations often recapitulate those found in various human neurological disorders not only underscoring the relevance of these models but also reinforcing the clinicopathogenetic significance of cytokines in diseases of the CNS.

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“…A role for IFN-␥ in the immune control of BDV in the CNS was suggested by recent experiments with transgenic mice expressing interleukin-12 (IL-12) in cerebellar astrocytes (32). Further, the multiplication of BDV was suppressed by IFN-␥ in organotypic slice cultures from mouse brains (18). We now demonstrate that IFN-␥ is essential for the in vivo control of BDV in mice and for the efficient elimination of the virus from neurons by CD8 T cells.…”

mentioning

confidence: 93%

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

Hausmann¹,

Pagenstecher

Baur³

et al. 2005

J Virol

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Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-␥) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-␥-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-␥-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-␥-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-␥ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-␥ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

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Borna Disease Virus Multiplication in Mouse Organotypic Slice Cultures Is Site-Specifically Inhibited by Gamma Interferon but Not by Interleukin-12

Cited by 20 publications

References 23 publications

Akt and c-Myc Induce Stem-Cell Markers in Mature Primary p53−/− Astrocytes and Render These Cells Gliomagenic in the Brain of Immunocompetent Mice

Akt and c-Myc Induce Stem-Cell Markers in Mature Primary p53−/− Astrocytes and Render These Cells Gliomagenic in the Brain of Immunocompetent Mice

Transgenic models for cytokine-induced neurological disease

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

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