Herpes simplex encephalitis in the temporal cortex and limbic system after trigeminal nerve inoculation.

Herpes simplex virus type 1 causes an encephalitis in humans that is primarily restricted to the temporal lobe and limbic system. The distribution of lesions suggests that virus enters the brain from a single site and then spreads transneuronally to infect connected structures. Two obvious sites of potential viral entry are the olfactory and trigeminal nerves. Trigeminal nerve entry is more likely because it innervates the oral cavity, a common site of initial infection, and the trigeminal ganglion is the most common site of viral latency. In previous reports, however, experimental trigeminal nerve infection has never led to the pattern of disease observed in humans. By directly inoculating virus into the murine tooth pulp, the mandibular division of the trigeminal nerve was selectively infected. This division, which innervates the oral cavity, is the one most commonly infected in humans. Intrapulp inoculation led to an encephalitis primarily affecting the temporal cortex and limbic system. Thus, spread via the trigeminal nerve provides an explanation for the distribution of herpes simplex virus observed in the human encephalitis.

Viral infection and dissemination through the olfactory pathway and the limbic system by Theiler's virus.

Theiler's murine encephalomyelitis virus (TMEV) infection of mice can produce a biphasic disease of the central nervous system (CNS). Most susceptible strains of mice survive the acute infection and develop a chronic demyelinating disease. In this report, we analyzed the routes of spread of TMEV within the CNS of nude mice and target sites eventually infected in the CNS. Compared to the immunocompetent mouse, in which an antiviral immune response is mounted but virus persists, the nude mouse develops a severe encephalomyelitis due to the lack of functional T lymphocytes and provides a useful model for the study of viral dissemination. We demonstrated, by immunohistochemistry, the presence of viral antigen in defined regions of the CNS, corresponding to various structures of the limbic system. In addition, we found a different time course for viral spread using two different sites of intracerebral inoculation, ie, via the olfactory bulb or the cortex. Limbic structures were rapidly infected following olfactory bulb infection and then showed a decrease in viral load, presumably due to loss of target neurons. Using either route of infection, the virus was able to disseminate to similar regions. These results indicate that limbic structures and their connections are very important for the spread of TMEV in the brain. In the spinal cord, not only neuronal but hematogenous pathways were suspected to be involved in the dissemination of Theiler's virus.

Isolation and characterization of Borna disease agent cDNA clones.

Borna disease (BD) is a neurologic syndrome characterized by behavioral disturbances and the accumulation of specific proteins in limbic system neurons. A viral etiology has been proposed because BD can be induced in birds, rodents, and primates by inoculation with filtered brain homogenates from animals with BD. We report here the isolation and preliminary characterization of cDNA clones from a rat with BD. These clones hybridized to specific transcripts in BD rat brain and arrested in vitro translation of BD proteins. In situ hybridization experiments using RNA probes prepared from these clones showed an abundance of these transcripts in limbic system neurons. Northern (RNA) hybridizations using these RNA probes indicated that the BD agent is probably a virus with major transcripts of 8.5, 2.1, and 0.8 kilobases.

Limbic encephalitis after inhalation of a murine coronavirus.

The spread of a neurotropic coronavirus, mouse hepatitis virus strain A59, in the mouse central nervous system was studied after intranasal inoculation. Mouse hepatitis virus strain A59 spread during the 3- to 5-day postinoculation period, through the olfactory pathway into the limbic system. Coronavirus particles were detected in the limbic system by electron microscopy. The combination of temporal propagation through an anatomical-physiological central nervous system pathway and anatomical restriction of viral infection suggests that specific interneuronal transport is important in spread of the virus. This experimental system may represent a model for diseases associated with human coronaviruses (common cold viruses) and/or the human limbic system.

[Borna virus infection (Borna disease) in naturally and experimentally infected animals: its significance for research and practice]. / Borna-Virus-Infektion (Borna-Krankheit) bei natürlich und experimentell infizierten Tieren: ihre Bedeutung für Forschung und Praxis.

In this survey article on Borna Disease-many years after the review of Zwick (1939)-again a modern comprehensive summary of "Borna Disease virus infection" is given. The infection occurs in horses and sheep, furthermore, in laboratory animal species inoculated experimentally; its clinical, virological and neuropathological features have been described in numerous presentations. Clinical symptoms in naturally and experimentally infected animals are characterized by initial alterations in the sensorium. The neurological symptomatology of the disease (disturbances in coordination, motor, sensory and vegetative symptoms) reflect the presumed localisation of the virus in various brain areas and the course of the disease supports the assumption of intraneural spread of the agent. In horses the incidence is highest during spring. Experimental infections show an exceptionally broad spectrum of infectible animals extending from higher mammals to birds. Our investigations make it clear that we have to differentiate between infections followed by disease (e.g. horse, rabbit, older rat) and persistent infections without overt clinical symptoms (mouse, chicken). Persistent infections are sometimes associated with fine alterations in behaviour (tree shrew) or decreased learning ability (mice). Borna Disease virus, which has not been characterized up to now, is known to grow without any cytopathic effect in tissue cultures. All tested cell lines (including those from man) could be infected. The investigations indicate that Borna Disease virus comprises an enveloped RNS-containing agent. The infection induces the production of specific antigens such as a complex known as the soluble antigen, and a 14500 dalton protein. Under natural conditions and in experimentally infected animals antibodies are produced against such soluble proteins and determinants involved in neutralization of the virus. In the central nervous system (CNS) a local immune response accompanied by the production of oligoclonal immunoglobulins is demonstrable. Besides the humoral reaction it was possible to study the influence of cellular defence mechanisms on the disease process in monkeys, rats and rabbits. Histopathologically, Borna Disease is characterized by a non-purulent inflammation of the brain and the spinal cord. Most alterations are found in the grey matter, mainly in the Ammon's horn, olfactory lobe, caudate nucleus, thalamus, lamina quadrigemina and in he cerebellar nuclei. The perivascular infiltrations, consisting of lymphocytes, histiocytes and plasma cells are most conspicuous. Occasionally, degenerative alterations are observed in ganglion cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Ultrastructural localization of viral antigens in the CNS of mice persistently infected with lymphocytic choriomeningitis virus (LCMV).

Lymphocytic choriomeningitis virus (LCMV) produces a persistent infection of the nervous system in susceptible mice. To map the localization of viral antigens in the central nervous system (CNS), the authors studied, by means of ultrastructural immune peroxidase techniques, 4-6-month-old mice persistently infected with LCMV following an intracerebral inoculation at birth. The greatest number of infected neurons was observed in the cortex, particularly of the limbic system, and certain nuclei of the hypothalamus. In the cerebellum, Purkinje cells selectively expressed viral antigens. Moderate numbers of infected neurons were found in the anterior horns of the spinal cord, basal ganglia, and thalamus. The immunoperoxidase technique using monoclonal antibodies showed that persistently infected neurons primarily expressed the nucleocapsid protein antigens of LCMV. Glycopeptide antigens were minimally expressed. Electron-microscopic examination of selected individual infected neurons showed viral antigens exclusively associated with ribosomes. No staining was seen on cell surfaces. Glutaraldehyde-fixed CNS tissue studied by electron microscopy did not reveal morphologic abnormalities or mature viral particles. This study demonstrates that LCMV persistently infects specific neuronal populations. Infected neurons express viral antigens in association with host ribosomes and show no significant morphologic alterations.