Mechanisms of Virus-Induced Neuronal Damage and the Clearance of Viruses from the CNS
The pathogenic mechanisms underlying virus-induced neurological disease are complex but fall into two general categories, neuronal damage or dysfunction, resulting: (1) from within, as a direct consequence of the virus infection, and (2) from without, due
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Introduction.
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2 CNS Response to Infection.
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3 Virus-CNS Interaction in Rabies.
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4 Virus-CNS Interaction in Borna Disease ..
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5 Mechanisms of Virus Clearance from the CNS .
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6 Outlook.
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References ..
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1 Introduction The pathogenic mechanisms underlying virus-induced neurological disease are complex but fall into two general categories, neuronal damage or dysfunction, resulting: (1) from within, as a direct consequence of the virus infection, and (2) from without, due to the indirect action of resident and invading immune/inflammatory cells responding to viral antigens. Our studies have focused on two viruses that can cause acute, lethal neurological diseases representative of these classes: rabies virus (RV) and Borna disease virus (BOV). RV infection induces significant electrophysiological changes in the CNS and sleep alterations but is accompanied by only minor histopathological changes in the CNS (GOURMELON et al. 1986, 1991). In contrast, acute Borna disease is associated with extensive neuropathology including astrogliosis, perivascular cuffing, monocytic infiltration of the brain parenchyma, and massive neuronal loss (RICHT et al. 1990; GOSZTONYI and LUDWIG 1995; STITZ et al. 1995; MORIMOTO et al. 1996), which are dependent on a BOV -specific immune response. The profound difference in the pathogenesis of rabies and Borna disease is evidenced by the fact that immunosuppression either has no effect or is detrimental to the outcome of rabies infection but is therapeutic Center for Neurovirology, Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107-6799, USA e-mail: bdietzscholdCareddi l.uns.tju.edu
G. Gosztonyi (ed.), The Mechanisms of Neuronal Damage in Virus Infections of the Nervous System © Springer-Verlag Berlin Heidelberg 2001
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in Borna disease (STITZ et al. 1995; MORIMOTO et al. 1996). Despite the clear differences in neuropathology between rabies and Borna disease, there are immune strategies for each that can evidently clear these viruses from the eNS thereby preventing a lethal outcome to the infections (DIETZSCHOLD et al. 1992; DIETZSCHOLD 1993; RICHT 1994). Further knowledge of the different pathogenic processes underlying rabies and Borna disease is key to the development of therapeutic strategies for diverse eNS viral diseases. In this chapter we discuss the response of eNS resident cells to infection, the link between these responses and the induction of virus-specific immunity, and the mechanisms through which virus can be cleared from the eNS.
2 eNS Response to Infection An interesting characteristic of RY and BDY infections is an almost undetectably low replication rate in the first half of the incubation period, which may reflect the relatively quiescent metabolic state of the neuron at the initiation of infection. During this time, viral RNA can only be detected using the reverse transcriptasepolymerase chain reaction (RT-PCR) (SHANKAR et al. 1991, 1992). After thi
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