Neal Nathanson

Immunosuppression and experimental virus infection of the nervous system.

n Publisher Summaryn n This chapter describes the current views of the pathogenesis of virus infections of the nervous system, with particular attention to certain aspects of virus-host interactions. Following invasion of the central nervous system, infection can follow a variety of patterns, as to number and distribution of neuronal and non-neuronal cells involved. There is a corresponding diversity in the pathological lesions of the central nervous system (CNS) produced by acute virus infection. Infection can be pictured as a race between virus and host defenses, where many factors, acting through different mechanisms, can influence the outcome. Outcome is always determined by multiple virus and host variables, although single variables can be independently studied under experimentally controlled conditions in the laboratory. The chapter demonstrates that in many virus-host combinations, the immune response plays an important role in recovery from primary infections. It mentions that an immunopathological process mediates the disease which follows certain CNS virus infections.n n

Antigenic Drift in Visna: Virus Variation During Long-term Infection of Icelandic Sheep

A group of 20 Icelandic sheep were infected intracerebrally with visna virus strain 1514, and 209 virus isolates were obtained from the blood, cerebrospinal fluid, and central nervous system (CNS) over a period of 7 years, during which eight animals developed clinical signs of visna necessitating sacrifice. (i) Using type-specific antisera, it was found that 12 (16%) of 76 isolates tested escaped neutralization. These 12 variant viruses were distributed randomly among animals and over time, and did not replace the infecting strain even though all sheep developed homotypic antibody within 3 months of infection. The one exception was sheep no. 1557 (an animal without clinical visna), where the last six isolates were variants. (ii) A total of 35 blood and CNS isolates from seven of these sheep (including five with clinical visna) were tested against serial samples of their own sera. Autologous antisera neutralized all isolates tested with the exception of isolates from sheep 1557. None of the isolates obtained at sacrifice from the five sheep with clinical visna escaped neutralization with autologous antisera. These data suggest that although variant viruses are encountered at considerable frequency during long-term infection of Icelandic sheep, the variants usually do not replace the infecting strain. Antigenic drift does not appear to be essential for virus persistence or for the development of clinically evident CNS lesions.

Experimental encephalitis following peripheral inoculation of West Nile virus in mice of different ages.

Experimental arbovirus infections of mice provide a convenient model to study factors which determine the occurrence or severity of encephalitis following extraneural infection with certain neurotropic viruses. Varying doses of West Nile or Powassan viruses were inoculated by intraperitoneal or intramuscular routes into mice of varing ages; individual variables were manipulated to influence the outcome of infection. Three patterns of pathogenesis were delineated: (1) Fatal encephalitis, preceded by early viraemia, and invasion of the central nervous system. (2) Inapparent infection, with no detectable viraemia and no evidence of central nervous system invasion. (3) Subclinical encephalitis, usually preceded by trace viraemia, with minimal transient levels of virus in the brain. In this latter type of subclinical infection with a potentially lethal virus, the immune response probably plays an important role in recovery.

Cerebellar Hypoplasia in Neonatal Rats Caused by Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis virus, strain E-350, when inoculated intracerebrally in rats 1 to 7 days old, produces an acute destructive infection of the cerebellar cortex resulting in permanent cerebellar hypoplasia and ataxia. Several other arenoviruses may produce a similar lesion in neonatal rodents.

The effect of post-infection immunization on the severity of experimental visna

Abstract Visna is a slow retrovirus infection of sheep which produces both inflammatory and demyelinating lesions of the central nervous system. A prior study indicated that immunosuppression markedly reduced the early inflammatory lesions. To further explore immunological determinants in the pathogenesis of visna, infected sheep were immunized 3 and 5 weeks after intracerebral virus infections and killed at 8 to 9 weeks. When infected autologous cells in Freunds complete adjuvant (FCA) were used as immunogen, there was no evidence of an accelerated immune response and no effect on lesion severity. When purified concentrated virus in FCA was used as immunogen, there was an accelerated immune response and a modest increase in lesion severity. Because visna virus replication is very slow in vivo, it was hypothesized that the extent of the antigen target might be a limiting parameter in disease progression. Comparison of 2 virus inocula, 10 8 and 10 5 TCD50, indicated that the larger dose was associated with more severe lesions. This is consistent with the view that the size of antigen target limits lesion severity, and could explain why immunization has only a modest influence on the extent of CNS pathology.

PATHOGENESIS OF CEREBELLAR HYPOPLASIA PRODUCED BY LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTION OF NEONATAL RATS: 1. EVOLUTION OF DISEASE FOLLOWING INFECTION AT 4 DAYS OF AGE

Intracerebral inoculation of 4-day-old rats with LCM virus (Armstrong E-350 strain) resulted in a severe cerebellar necrosis and consequent ataxia. The pathogenesis of this disease was studied using virological, serological, and histological methods. Cerebellar necrosis occurred concomitantly with an acute and severe transitory choriomeningitis. While neural structures involved in postnatal replication were heavily infected, only the cerebellum consistently showed pathological changes. Necrosis was first evident in the granule cells, with secondary loss of Purkinje cells and white matter, but with sparing of the deep cerebellar nuclei. Brain virus reached high titers early after infection and gradually decreased finally to disappear 5 months after inoculation. Viremia was minimal and transitory, occurring within two weeks of infection. Although complement fixing antibodies developed, their relation to the cerebellar lesion is questionable since the pathology was well established prior to the occurrence of detectable levels of antibody. In addition, the acute phase of infection was associated with a retardation in growth rate, the consequence of which was a permanent impairment in development reflected by reduced brain and body weights.

Potentiation of Experimental Arbovirus Encephalitis by Immunosuppressive Doses of Cyclophosphamide

THE role of the immune response in recovery from primary viral infection has been debated for many years, in part because of the inconclusive nature of the relevant evidence1,2. The ability of children with defective immunoglobulin synthesis to recover uneventfully from certain viral infections3, and the recognition of non-immune host defences such as interferon4, have suggested that the immune response plays a small part. The recent development of an increasing variety of techniques for the production of immunosuppression permits a re-examination of the question. Using the potent alkylating agent, cyclophosphamide5,6, we have found that administration of immunosuppressive doses of the drug converts a silent abortive arbovirus infection of the rodent central nervous system (CNS) into a lethal encephalitis.

Viral Hemorrhagic Encephalopathy of Rats

A virus has been isolated and serially passed in suckling rats; it causes an acute fatal paralysis associated with hemorrhage and necrosis in the brain and spinal cord. The agent is relatively resistant to heat and ether, is about 20 millimicrons in diameter, and is antigenically closely related to rat virus. Its isolation resulted from the study of occasional cases of paralysis in adult rats after administration of cyclophosphamide.

The surveillance of poliomyelitis in the United States in 1955

The role of the Public Health Service in the poliomyelitis problems of 1955 may be grouped into three main activities: (1) the licensing of products and producers and the clearance of vaccines; (2) the administration of federal grant-in-aid funds and of the voluntary interstate program for the distribution of vaccine; and (3) the surveillance of the disease and the field evaluation of the safety and effectiveness of vaccines. The present report will be limited to the surveillance activities. The National Poliomyelitis Surveillance Program was created by the Surgeon General of the Public Health Service on April 28, 1955, immediately after the recognition that cases of poliomyelitis were occurring in association with vaccine manufactured by Cutter Laboratories. The purpose of the program

Pathogenesis of Visna. IV. Spinal Fluid Studies

Visna is a persistent retrovirus infection of sheep which produces a chronic progressive paralytic disease after an incubation period lasting from months to years. The cerebrospinal fluid (CSF) was repeatedly sampled in a group of Icelandic sheep which were infected intracerebrally and followed up to 42 months. Minimal levels of infectious virus were isolated from the cerebrospinal fluid (CSF) up to 4 months after infection after which CSF neutralizing antibodies appeared in many sheep. These antibodies varied in titer and in some animals exceeded serum antibody levels which were moderate to high. CSF antibody is apparently produced within the CNS by local proliferation of B cell clones, and is accompanied by the appearance of considerable numbers of plasma cells in the neural parenchyma. Some sheep raised serum antibody to a second serotype of visna virus and in a number of these animals heterotypic antibody was also found in the CSF. An increase in CSF leukocytes often occurs within 1 to 3 months following infection and may then persist or wane. A persistent high level of CSF cells is an indicator of progressive CNS disease and such animals are more likely to yield virus, have higher CSF antibody levels, more severe CNS lesions, and an enhanced risk of clinical illness (progressive paralysis). CSF cells are predominantly macrophages and lymphocytes, with a consistent minority of plasma cells.