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

2005 ◽  
Vol 79 (21) ◽  
pp. 13509-13518 ◽  
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.

scholarly journals CD8+ T Lymphocytes Mediate Borna Disease Virus-Induced Immunopathology Independently of Perforin

2001 ◽  
Vol 75 (21) ◽  
pp. 10460-10466 ◽  
Author(s):  
Jürgen Hausmann ◽  
Karin Schamel ◽  
Peter Staeheli
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Disease Virus ◽  
Target Cells ◽  
Wild Type ◽  
Pathogenic Potential ◽  
Borna Disease Virus ◽  
Viral Spread ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Perforin-mediated lysis of target cells is the major antiviral effector mechanism of CD8+ T lymphocytes. We have analyzed the role of perforin in a mouse model for CD8+T-cell-mediated central nervous system (CNS) immunopathology induced by Borna disease virus. When a defective perforin gene was introduced into the genetic background of the Borna disease-susceptible mouse strain MRL, the resulting perforin-deficient mice developed strong neurological disease in response to infection indistinguishable from that of their perforin-expressing littermates. The onset of disease was slightly delayed. Brains of diseased perforin-deficient mice showed similar amounts and a similar distribution of CD8+ T cells as wild-type animals. Perforin deficiency had no impact on the kinetics of viral spread through the CNS. Unlike brain lymphocytes from diseased wild-type mice, lymphocytes from perforin-deficient MRL mice showed no in vitro cytolytic activity towards target cells expressing the nucleoprotein of Borna disease virus. Taken together, these results demonstrate that CD8+ T cells mediate Borna disease independent of perforin. They further suggest that the pathogenic potential of CNS-infiltrating CD8+ T cells does not primarily reside in their lytic activity but rather in other functions.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals Virus-Specific CD4+ T Cells Eliminate Borna Disease Virus from the Brain via Induction of Cytotoxic CD8+T Cells

1998 ◽  
Vol 72 (5) ◽  
pp. 4387-4395 ◽  
Author(s):  
Kerstin Nöske ◽  
Thomas Bilzer ◽  
Oliver Planz ◽  
Lothar Stitz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Disease Virus ◽  
Target Cells ◽  
Borna Disease Virus ◽  
Infected Control ◽  
Low Level ◽  
The Brain ◽  
Borna Disease

ABSTRACT Persistent Borna disease virus infection of the brain can be prevented by treatment of naive rats with a virus-specific CD4+ T-cell line prior to infection. In rats receiving this treatment, only a transient low-level encephalitis was seen compared to an increasingly inflammatory reaction in untreated infected control rats. Virus replication was found in the brain for several days after infection before the virus was cleared from the central nervous system. The loss of infectivity from the brain was confirmed by negative results by reverse transcription-PCR with primers for mRNA, by in situ hybridization for both genomic and mRNA, and by immunohistology. Most importantly, in vitro assays revealed that the T-cell line used for transfusion had no cytotoxic capacity. The kinetics of virus clearance were paralleled by the appearance of CD8+ T cells and the expression of perforin in the brain. Testing of lymphocytes isolated from the brains of CD4+T-cell-treated rats after challenge revealed high cytotoxic activity due to the presence of CD8+ cytotoxic T cells at time points when brain lymphocytes from infected control rats induced low-level cytolysis of target cells. Neutralizing antiviral antibodies and gamma interferon were shown not to be involved in the elimination of virus from the brain.

scholarly journals Gamma Interferon-Induced Inhibition ofToxoplasma gondii in Astrocytes Is Mediated by IGTP

2001 ◽  
Vol 69 (9) ◽  
pp. 5573-5576 ◽  
Author(s):  
Sandra K. Halonen ◽  
Gregory A. Taylor ◽  
Louis M. Weiss
Keyword(s):  
Immunoblot Analysis ◽  
Significant Inhibition ◽  
Gamma Interferon ◽  
Wild Type ◽  
Effector Cells ◽  
Inhibition Of Growth ◽  
The Central Nervous System ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice

ABSTRACT Toxoplasma gondii is an important pathogen in the central nervous system, causing a severe and often fatal encephalitis in patients with AIDS. Gamma interferon (IFN-γ) is the main cytokine preventing reactivation of Toxoplasma encephalitis in the brain. Microglia are important IFN-γ-activated effector cells controlling the growth of T. gondii in the brain via a nitric oxide (NO)-mediated mechanism. IFN-γ can also activate astrocytes to inhibit the growth of T. gondii. Previous studies found that the mechanism in murine astrocytes is independent of NO and all other known anti-Toxoplasma mechanisms. In this study we investigated the role of IGTP, a recently identified IFN-γ-regulated gene, in IFN-γ inhibition of T. gondii in murine astrocytes. Primary astrocytes were cultivated from IGTP-deficient mice, treated with IFN-γ, and then tested for anti-Toxoplasma activity. In wild-type astrocytesT. gondii growth was significantly inhibited by IFN-γ, whereas in astrocytes from IGTP-deficient mice IFN-γ did not cause a significant inhibition of growth. Immunoblot analysis confirmed that IFN-γ induced significant levels of IGTP in wild-type murine astrocytes within 24 h. These results indicate that IGTP plays a central role in the IFN-γ-induced inhibition of T. gondii in murine astrocytes.

scholarly journals T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with DisseminatedChlamydia muridarumGenital Tract Infection

2018 ◽  
Vol 86 (7) ◽  
pp. e00143-18 ◽  
Author(s):  
Taylor B. Poston ◽  
Catherine M. O'Connell ◽  
Jenna Girardi ◽  
Jeanne E. Sullivan ◽  
Uma M. Nagarajan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tract Infection ◽  
B Cell ◽  
Gamma Interferon ◽  
Wild Type ◽  
Content Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTCD4 T cells and antibody are required for optimal acquired immunity toChlamydia muridarumgenital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice withC. muridarumCM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal forSTAT1−/−andIFNG−/−mice, in which IFN-γ signaling was absent, and forRag1−/−mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM toRag1−/−mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescuedRag1−/−mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

scholarly journals Vaccine-induced protection against Borna disease in wild-type and perforin-deficient mice

2005 ◽  
Vol 86 (2) ◽  
pp. 399-403 ◽  
Author(s):  
Jürgen Hausmann ◽  
Karen Baur ◽  
Karin R. Engelhardt ◽  
Timo Fischer ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurological Disease ◽  
Cell Epitope ◽  
Wild Type ◽  
Immune Priming ◽  
Boost Immunization ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

Borna disease virus (BDV) can persistently infect the central nervous system and induce CD8+ T-cell-mediated neurological disease in MRL mice. To determine whether specific immune priming would prevent disease, a prime–boost immunization protocol was established in which intramuscular injection of a recombinant parapoxvirus expressing BDV nucleoprotein (BDV-N) was followed by intraperitoneal infection with vaccinia virus expressing BDV-N. Immunized wild-type and perforin-deficient mice remained healthy after intracerebral infection with BDV and contained almost no virus in the brain at 5 weeks post-challenge. Immunization failed to induce resistance against BDV in mice lacking mature CD8+ T cells. Immunization of perforin-deficient mice with a poxvirus vector expressing mutant BDV-N lacking the known CD8+ T-cell epitope did not efficiently block multiplication of BDV in the brain and did not prevent neurological disease, indicating that vaccine-induced immunity to BDV in wild-type and perforin-deficient mice resulted from the action of CD8+ T cells.

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

2004 ◽  
Vol 78 (3) ◽  
pp. 1212-1218 ◽  
Author(s):  
Gregor Friedl ◽  
Markus Hofer ◽  
Bernd Auber ◽  
Christian Sauder ◽  
Jürgen Hausmann ◽  
...  
Keyword(s):  
Disease Virus ◽  
Hippocampal Slice ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Borna Disease Virus ◽  
Hippocampal Slice Cultures ◽  
Organotypic Slice Cultures ◽  
Ifn Γ ◽  
Borna Disease

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.

scholarly journals Antiviral CD8 T Cells Recognize Borna Disease Virus Antigen Transgenically Expressed in either Neurons or Astrocytes

2008 ◽  
Vol 82 (6) ◽  
pp. 3099-3108 ◽  
Author(s):  
Karen Baur ◽  
Mathias Rauer ◽  
Kirsten Richter ◽  
Axel Pagenstecher ◽  
Jürgen Götz ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Virus ◽  
Cd8 T Cells ◽  
Neurological Disease ◽  
Active Role ◽  
Cell Types ◽  
Virus Antigen ◽  
Immune Recognition ◽  
Borna Disease Virus ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) can persistently infect the central nervous system (CNS) of mice. The infection remains nonsymptomatic as long as antiviral CD8 T cells do not infiltrate the infected brain. BDV mainly infects neurons which reportedly carry few, if any, major histocompatibility complex class I molecules on the surface. Therefore, it remains unclear whether T cells can recognize replicating virus in these cells or whether cross-presentation of viral antigen by other cell types is important for immune recognition of BDV. To distinguish between these possibilities, we used two lines of transgenic mice that strongly express the N protein of BDV in either neurons (Neuro-N) or astrocytes (Astro-N). Since these animals are tolerant to the neo-self-antigen, we adoptively transferred T cells with specificity for BDV N. In nontransgenic mice persistently infected with BDV, the transferred cells accumulated in the brain parenchyma along with immune cells of host origin and efficiently induced neurological disease. Neurological disease was also observed if antiviral T cells were injected into the brains of Astro-N or Neuro-N but not nontransgenic control mice. Our results demonstrate that CD8 T cells can recognize foreign antigen on neurons and astrocytes even in the absence of infection or inflammation, indicating that these CNS cell types are playing an active role in immune recognition of viruses.

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