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

ABSTRACT Borna disease virus (BDV) induces a nonpurulent CD4- and CD8-T-cell-dependent meningoencephalitis in susceptible animals. Upon intracerebral infection, BDV replicates in the mouse central nervous system (CNS), but only a few mouse strains develop neurological disorder. The antiviral T cells appear to suppress BDV replication by a noncytolytic mechanism. Since BDV does not replicate in standard mouse cell cultures, the putative role of gamma interferon (IFN-γ) in virus control could not be tested experimentally. Here, we report that mouse organotypic slice cultures can be used to elucidate the complex interactions of BDV, the CNS, and the immune system. We show that BDV replicated in various cell types of mouse cerebellar slice cultures in vitro. In infected slice cultures, a moderate upregulation of the chemokine genes CCL5 and CXCL10 was observed, while expression of various neural genes as well as other chemokine and cytokine genes was not altered. IFN-γ inhibited the multiplication of BDV in cerebellar and hippocampal slice cultures in a dose-dependent manner. However, while complete suppression of BDV was observed in cerebellar slice cultures, inhibition was incomplete in hippocampal slice cultures. Kinetic studies indicated that IFN-γ protects noninfected cells from infection rather than clearing the virus from infected cells. These results demonstrate that BDV can replicate in cultured neural cells of the mouse if organ integrity is well preserved. They further show that IFN-γ is a powerful inhibitor of BDV in the absence of blood-borne leukocytes in mouse cerebellar slice cultures.

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

Journal of Virology ◽

10.1128/jvi.79.21.13509-13518.2005 ◽

2005 ◽

Vol 79 (21) ◽

pp. 13509-13518 ◽

Cited By ~ 31

Author(s):

Jürgen Hausmann ◽

Axel Pagenstecher ◽

Karen Baur ◽

Kirsten Richter ◽

Hanns-Joachim Rziha ◽

...

Keyword(s):

T Cells ◽

Disease Virus ◽

Cd8 T Cells ◽

Gamma Interferon ◽

Wild Type ◽

Borna Disease Virus ◽

Ifn Γ ◽

The Brain ◽

Deficient Mice ◽

Borna Disease

ABSTRACT 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-γ) 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-γ-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-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-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-γ 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-γ 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 Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

Journal of Virology ◽

10.1128/jvi.76.23.12223-12232.2002 ◽

2002 ◽

Vol 76 (23) ◽

pp. 12223-12232 ◽

Cited By ~ 16

Author(s):

Susanna Freude ◽

Jürgen Hausmann ◽

Markus Hofer ◽

Ngan Pham-Mitchell ◽

Iain L. Campbell ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Transgenic Mice ◽

Disease Virus ◽

Biologically Active ◽

Interleukin 12 ◽

Wild Type ◽

Borna Disease Virus ◽

The Central Nervous System ◽

Borna Disease

ABSTRACT Targeted expression of biologically active interleukin-12 (IL-12) in astrocytes of the central nervous system (CNS) results in spontaneous neuroimmunological disease of aged mice. Borna disease virus (BDV) can readily multiply in the mouse CNS but does not trigger disease in most strains. Here we show that a large percentage of IL-12 transgenic mice developed severe ataxia within 5 to 10 weeks after infection with BDV. By contrast, no disease developed in mock-infected IL-12 transgenic and wild-type mice until 4 months of age. Neurological symptoms were rare in infected wild-type animals, and if they occurred, these were milder and appeared later. Histological analyses showed that the cerebellum of infected IL-12 transgenic mice, which is the brain region with strongest transgene expression, contained large numbers of CD4+ and CD8+ T cells as well as lower numbers of B cells, whereas other parts of the CNS showed only mild infiltration by lymphocytes. The cerebellum of diseased mice further showed severe astrogliosis, calcifications and signs of neurodegeneration. BDV antigen and nucleic acids were present in lower amounts in the inflamed cerebellum of infected transgenic mice than in the noninflamed cerebellum of infected wild-type littermates, suggesting that IL-12 or IL-12-induced cytokines exhibited antiviral activity. We propose that BDV infection accelerates the frequency by which immune cells such as lymphocytes and NK cells enter the CNS and then respond to IL-12 present in the local milieu causing disease. Our results illustrate that infection of the CNS with a virus that is benign in certain hosts can be harmful in such normally disease-resistant hosts if the tissue is unfavorably preconditioned by proinflammatory cytokines.

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Multiple Mechanisms Contribute to the Robust Rapid Gamma Interferon Response by CD8+ T Cells during Listeria monocytogenes Infection

Infection and Immunity ◽

10.1128/iai.01207-08 ◽

2009 ◽

Vol 77 (4) ◽

pp. 1492-1501 ◽

Cited By ~ 10

Author(s):

Elsa N. Bou Ghanem ◽

Denise S. McElroy ◽

Sarah E. F. D'Orazio

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Gamma Interferon ◽

Interferon Response ◽

In Vitro Assays ◽

Interleukin 12 ◽

Dependent Manner ◽

Listeriolysin O ◽

Ifn Γ ◽

Bacterial Products

ABSTRACT A subset of CD8+ T cells can rapidly secrete gamma interferon (IFN-γ) in an antigen-independent and interleukin-12 (IL-12)- and IL-18-dependent manner within 16 h of infection with the intracellular bacterial pathogen Listeria monocytogenes. This rapid IFN-γ response is robust enough to be detected directly ex vivo and is not observed following infection with intracellular bacterial pathogens that remain sequestered within host cell vacuoles. We demonstrate here that three distinct pathways can lead to rapid secretion of IFN-γ by CD8+ T cells during L. monocytogenes infection: (i) a direct cytokine-inducing activity encoded by the cholesterol-dependent cytolysin (CDC) listeriolysin O (LLO) acts within the infected cell, (ii) the pore-forming activity of LLO promotes cytosolic localization of bacterial products that trigger cytosol-specific signaling pathways, and (iii) the sustained presence of high concentrations of bacterial products can exogenously trigger cytokine production. Although it has been suggested that CDC protein toxins may act as Toll-like receptor 4 (TLR4) agonists to trigger proinflammatory cytokine secretion, we show in this report that TLR4 signaling is not required to induce a maximal rapid IFN-γ response by CD8+ T cells. The results presented here indicate that multiple mechanisms contribute to the induction of rapid IFN-γ secretion by CD8+ T cells during Listeria infection and that care must be taken when interpreting the results of in vitro assays, since the contribution of each pathway can vary depending on how the assay is performed.

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Replication-Defective Adenovirus Infection ReducesHelicobacter felis Colonization in the Mouse in a Gamma Interferon- and Interleukin-12-Dependent Manner

Infection and Immunity ◽

10.1128/iai.67.9.4539-4544.1999 ◽

1999 ◽

Vol 67 (9) ◽

pp. 4539-4544 ◽

Cited By ~ 25

Author(s):

Bo Jiang ◽

Manel Jordana ◽

Zhou Xing ◽

Fionna Smaill ◽

Denis P. Snider ◽

...

Keyword(s):

Immune Response ◽

Viral Infection ◽

Animal Studies ◽

Gamma Interferon ◽

Interleukin 12 ◽

Mouse Strains ◽

Dependent Manner ◽

Th2 Immune Response ◽

Ifn Γ ◽

Replication Defective Adenovirus

ABSTRACT Helicobacter infection leads to chronic inflammation of the stomach. Although the infection persists in spite of an immune response, animal studies have shown that adjuvant-based oral vaccines can protect against infection and even eliminate established infection. These vaccines are thought to induce a Th2 immune response, counterbalancing the Th1 response seen with natural infections. As a prelude to using adenovirus vectors carrying cytokine genes to modulate the immune response to established Helicobacter felisinfection, we first examined the effect of the replication-defective adenovirus (RDA) vector itself. C57BL/6 mice chronically infected withH. felis (8 to 10 weeks) received intramuscular injections of RDA. The effect of RDA on the severity of H. feliscolonization and the degree of gastric inflammation was assessed 2 weeks later. RDA caused a significant decrease in H. feliscolonization without significantly altering the associated inflammation. RDA did not alter the H. felis-specific immunoglobulin G1 (IgG1), IgG2a, and IgA responses in the serum but was associated with an increase in gamma interferon (IFN-γ)-producing CD8+ spleen cells. To determine if IFN-γ or Th1 cytokines were involved in the response to RDA, we examined RDA treatment ofH. felis infection in mice lacking either IFN-γ or interleukin-12 (IL-12). RDA failed to alter H. feliscolonization in either of these two mouse strains. Thus, viral infection of mice chronically infected with H. felis led to a significant decrease in H. felis colonization in an IFN-γ- and IL-12-dependent manner. These results demonstrate that Th1 responses associated with systemic viral infection can influence an established H. felis infection.

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