Biomedical subjects
Publications and source records attributed to A A Monjan.
Nine strains of mice bearing five distinct H-2 genotypes were inoculated intracerebrally with LCMV. There was no association found between particular K or D allotypes and susceptibility to acute LCM disease.
After mice were exposed to a daily auditory stressor for varying lengths of time, the responses of their splenic lymphoid cells in vitro were assessed. Both the blastogenic activity of concanavalin A or lipopolysaccharide and the ability of immune lymphocytes to lyse P815 target cells showed the same patterns of immunosuppression and enhancement.
Lymphocytic choriomeningitis (LCM) virus of the mice provides perhaps the most extensively studied model of viral-induced immunopathology. Intraocular inoculation of this virus in the adult mouse produces a severe and progressive uveitis with involvement also of the cornea and retina. Intracerebral infection of the newborn rat with LCM virus produces a severe retinopathy, with only minimal involvement of the uveal tract. We review in this paper recent studies on these two animal models of LCM virus disease which demonstrate: (1) the histopathology of the ocular lesion; (2) that immunosuppression after infection prevents development of the disease; (3) that passive transfer of sensitized lymphoid cells to the immunosuppressed infected animal can then trigger ocular disease, and (4) that T lymphocytes, and not circulating antibody, play the major role in the pathogenesis of this disease process.
In addition to the previously reported data on the retinal and cerebellar immunopathology following infection of neonatal rats with LCM virus, we have found that there are long-term effects on behavioural and neurological development. Rats were inoculated intracerebrally with the E-350 strain at different ages during the first 3 weeks after birth. Behavioural tests were initiated when the animals were either 3 months or 1 year of age. The behavioural consequences appear to be a long-term alteration in emotional reactivity such that the infected animals are less responsive than controls as assessed by these measures. No alterations were detected in animals infected after the first postnatal week. Complementing these data are the findings of a collaterally progressive lesion of the hippocampal dentate gyrus as well as a loss in total cell number in the forebrain (as assessed by DNA, RNA, and protein determinations) amounting to about 20% of the brain mass. These behavioural, histological, and biochemical data indicate that there are forebrain structures, most probably within the limbic system, that are susceptible at critical phases of development to the pathological consequences of infection with LCM virus.
Lymphocytic choriomeningitis virus, following inoculation of 4-day-old rats, produces an acute destructive but nonfatal necrosis of the cerebellum which is immunologically mediated. An ultrastructural study of the developing lesion indicated the following sequence of events: first, lymphocytic choriomengitis virions appear in the intercellular spaces of apparently normal neural parenchyma, followed shortly thereafter (5 days after infection) by adherence of monocytes to vascular endothelium with migration into tissue and morphologic transformation into activated macrophages, concomitant with necrosis of neural cells which progresses from 1 to 3 weeks after infection. Removal of debris overlaps with and is followed by astrogliosis, collagen deposition, and vascular changes. Finally, several months after infection, an increasing infiltration of plasma cells occurs, accompanied by gradual disappearance of virus from the neural parenchyma. These morphologic observations suggest that the acut immunopathology is cell-mediated whereas local antibody production may play an important role in clearance of virus from persistently infected tissue.
Intracerebral inoculation of 4-day-old rats with lymphocytic choriomeningitis virus (E-350 strain) produced a nonfatal, acute, severe, and permanent cerebellar necrosis with minimal histological evidence of inflammation. Virus persisted in the brain at high titers for 30 to 40 days and was finally cleared about 120 days after infection. Rabbit anti-rat lymphoid serum prevented cerebellar necrosis, and brain virus titers were higher than in control animals receiving normal rabbit serum. Thus, the immune response which clearly is responsible for the cerebellar lesion also plays a role in the gradual suppression of infection.
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A single dose of 150 mg/g of cyclophosphamide (CY), given 3 days after intracerebral (i.c.) inoculation of lymphocytic choriomeningitis (LCM) virus, protected over 90% of adult BALB/c mice against acutely fatal choriomeningitis. Surviving mice became persistently infected carriers, with high virus titers in blood and brain. Immunofluorescent examination of the brain showed that in CY-induced carriers infection was initially confined to the choroid plexus, ependyma, and leptomeninges, but over the next 30 days gradually spread to the neural parenchyma, most notably to the molecular layer of the cerebellum. By contrast, LCM virus-carrier mice produced by neonatal virus injection and examined as adults, showed a much less marked infection of choroid plexus and much more widespread infection of parenchyma, with a different distribution among brain nuclei, including heavy infection of the Purkinje cells of the cerebellum.
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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.
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