Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genes induced after BDV infection in Sprague Dawley and Lewis rats

ABSTRACT: Borna Disease Virus (BDV) is a neurotropic virus that persistently infects neurons in the central nervous system of various hosts, including rats. Although BDV is known to be an IFN sensitive virus, determination of the cellular mRNA transcript levels revealed the induction of IFN-stimulated genes in organotypic rat hippocampus slice cultures, raising the question how BDV evades this innate immune response. Using rat Mx protein as a specific marker for IFN-induced gene products, we could show that neurons lack detectable levels of Mx in these BDV infected cultures, whereas astrocytes and microglial cells were Mx positive. Neurons remained Mx negative after treatment of uninfected hippocampus cultures as well as primary dissociated neuronal cultures with high concentrations of IFN-M-NM-1. This non-responsiveness correlated with a lack of a detectable nuclear translocation of pSTAT1 in rat neurons. Consistently, IFN treatment of BDV-infected rat neurons did not prevent the establishment of a viral persistence in the neuronal tissue. However, IFN treatment efficiently prevented vesicular stomatitis virus (VSV) replication, indicating that these cells can mount a weak innate immune response. In contrast, IFN treatment of mouse neurons resulted in the upregulation of Mx1 proteins and inhibition of BDV replication, indicating species-specific differences in the IFN response in neurons between mice and rats. Rat neurons may therefore represent the ideal cell type for BDV to evade the innate immune in the central nervous system. To determine the mRNA levels in the hippocampal slice cultures after BDV infection in Sprague Dawley and Lewis rats Hippocampal slice cultures were prepared from newborn Lewis and SD rats (P0-P2). Half of the samples remained uninfected, whereas the other half was infected with 1000 focus forming units (FFU) of BDV strain He/80. Total RNA from a pool of 12 slice cultures was prepared

ORGANISM(S): Rattus norvegicus

SUBMITTER: Martin Schwemmle

PROVIDER: E-GEOD-41540 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Absence of a robust innate immune response in rat neurons facilitates persistent infection of Borna disease virus in neuronal tissue.

Lin Chia-Ching CC Wu Yuan-Ju YJ Heimrich Bernd B Schwemmle Martin M

Cellular and molecular life sciences : CMLS 20130623 22

Borna disease virus (BDV) persistently infects neurons of the central nervous system of various hosts, including rats. Since type I IFN-mediated antiviral response efficiently blocks BDV replication in primary rat embryo fibroblasts, it has been speculated that BDV is not effectively sensed by the host innate immune system in the nervous system. To test this assumption, organotypical rat hippocampal slice cultures were infected with BDV for up to 4 weeks. This resulted in the secretion of IFN an ...[more]

PMID: 23793543

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Project description:The major inducible 70 kDa heat shock protein (hsp70) is host protective in a mouse model of measles virus (MeV) brain infection. Transgenic constitutive expression of hsp70 in neurons, the primary target of MeV infection, abrogates neurovirulence in neonatal H-2d congenic C57BL/6 mice. A significant level of protection is retained after depletion of T lymphocytes, implicating innate immune mechanisms. Focus of the present work was to elucidate the basis for hsp70-dependent innate immunity using this model. Transcriptome analysis of brains from transgenic (TG) and non-transgenic (NT) mice 5 days after infection identified type 1 interferon (IFN) signaling and macrophage activation/antigen presentation as the main differences linked to survival. The pivotal role for type 1 IFN in hsp70-mediated protection was demonstrated in mice with a genetically disrupted type 1 IFN receptor (IFNAR-/-), where IFNAR-/- eliminated the difference in survival between TG and NT mice. Brain macrophages, not neurons, are the predominant source of type 1 IFN in the virus-infected brain, and in vitro studies provided a mechanistic basis by which MeV-infected neurons can induce IFN-β in uninfected microglia in an hsp70-dependent manner. MeV infection induced extracellular release of hsp70 from mouse neuronal cells that constitutively express hsp70, and extracellular hsp70 induced IFN-β transcription in mouse microglial cells through Toll-like receptors 2 and 4. Collectively, results support a novel axis of type 1 IFN-dependent antiviral immunity in the virus-infected brain that is driven by hsp70. Hsp70 expression in mice enhances gene expression related to antiviral immune response against MeV neurovirulence. We performed microarrays on whole brain tissues in mice to obtain an unbiased picture of how hsp70 alters host innate responses to viral infection. Hsp70-overexpressing transgenic (TG) and non-transgenic (NT) mice were infected with MeV intracranially, and total brain mRNA harvested at 5 and 10 days post infection (d.p.i.) was analyzed, sampling the hemisphere opposite the side of viral inoculation. Analysis includes 6 groups: infected TG at 5 d.p.i. (n=4), infected TG at 10 d.p.i. (n=5), infected NT at 5 d.p.i. (n=4), infected NT at 10 d.p.i. (n=5), uninfected TG at 5 d.p.i. (n=4), and uninfected NT at 5 d.p.i. (n=4).

Dataset Information

Genes induced after BDV infection in Sprague Dawley and Lewis rats

Publications

Absence of a robust innate immune response in rat neurons facilitates persistent infection of Borna disease virus in neuronal tissue.

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