Severity of lymphocytic choriomeningitis virus disease in different strains of suckling mice correlates with increasing amounts of endogenous interferon.

A marked difference was observed in the severity of disease in lymphocytic choriomeningitis (LCM) virus-infected suckling BALB/c, Swiss, and C3H mice. BALB/c mice had minimal liver lesions and none died, whereas C3H mice had extensive liver lesions and all mice died. An intermediate pattern was oberved for Swiss mice (36% mortality). Although there was no difference in the titers of LCM virus in the plasma or liver between these three strains of mice, there was a marked difference in the amount of interferon produced and the duration of interferonemia. C3H mice produced more interferon than Swiss mice which produced more interferon than BALB/c mice, indicating a direct correlation between the amount of interferon induced by LCM virus and the extent of disease. Inoculation of a potent anti-mouse interferon globulin markedly reduced the incidence of mortality in virus-infected C3H mice. BALB/c mice were as sensitive to the effects of interferon as C3H mice because daily administration of potent interferon preparations did induce disease in this strain. This ensemble of results supports our contention that endogenous interferon is in large part responsible for the manifestaions of acute LCM virus disease in suckling mice.

Rapid enrichment of mouse natural killer cells by use of wheat germ agglutinin.

The separation of mouse T and B lymphocytes by differential agglutination with wheat germ agglutinin (WGA) also enriches natural killer (NK) activity 2-7-fold. NK cells are recovered within the agglutinated cell population indicating that NK cells bind WGA. This technique can be applied to endogenous or interferon-induced NK cells.

Interferon-induced disease in mice and rats.

Treatment of newborn mice with potent mouse interferon preparations resulted in an acute "early" syndrome characterized by inhibition of growth, delay in maturation of several organs, diffuse liver cell necrosis and death. When interferon treatment was discontinued at 1 week of life, mice appeared to recover, but subsequently developed a progressive glomerulonephritis ("late syndrome"). Treatment of newborn rats with potent rat interferon preparations also resulted in inhibition of growth, delay in maturation, and the subsequent development of glomerulonephritis. After infection at birth with lymphocyte choriomeningitis (LCM) virus, most strains of mice developed a similar acute early syndrome and surviving mice subsequently developed glomerulonephritis. We postulated that the endogenous interferon induced by LCM virus early in life was partially responsible for these syndromes. Administration of a potent anti-mouse interferon serum to LCM virus-infected mice neutralized the circulating endogenous interferon and inhibited the development of both the early and late syndromes. Our results suggest that large amounts of exogenous or endogenous interferon at a crucial stage of rapid growth or development of mice and rats can induce lesions in several different organs. Some lesions (i.e. the kidney) only become apparent weeks or even months after exposure to interferon.

[Virological control of laboratory mice]. / Le contrôle virologique des souris de laboratoire

Virological control of laboratory mice can be obtained by serology or virus isolation from the animals. Advantages and inconveniencies of these two techniques are discussed. Special techniques i.e. preparation of immune sera or cultures of infected tissues, are also described.

Presence of specific antigens in neuronal cells infected with fixed and street rabies virus strains.

The presence of rabies specific antigens is investigated after infection with different rabies virus strains in neural cell lines and in the central nervous system of laboratory rodents. In fixed rabies infected cells, the rabies glycoprotein is found to be present 48 h after infection, whereas in hamsters this protein was found 5 days after an intracerebral inoculation. In contrast, rabies glycoprotein was not detectable in any of the street rabies-infected cell system by the fluorescent antibody test, although nucleoprotein was present, showing that infection occurred in these cells. Rabies glycoprotein was also undetectable in the central nervous system (CNS) of athymic nude mice which is known to be very sensitive to street rabies infection and to contain large quantities of viral material. Our results suggest that the smaller amount of rabies glycoprotein synthesized during street rabies infection are of consequence for the pathogenesis of rabies disease. The immunopathology of street rabies virus infection is certainly modulated by the failure of the viral glycoprotein to be present in large quantities on the surface of the infected cellular membrane as in the case of fixed rabies.

An orbivirus of mosquitoes which induces CO2 sensitivity in mosquitoes and is lethal for rabbits.

An orbivirus, JKT-7400, isolated from Culex mosquitoes in Indonesia, replicated to a high titer and induced cytopathic effects in Aedes albopictus cell cultures. The virus produced lethal sensitivity to carbon dioxide in Culex and Aedes mosquitoes as well as in Drosophila melanogaster fruit flies but was not the agent of the hereditary sensitivity to carbon dioxide previously described for Culex quinquefasciatus. When injected intravenously in high doses, JKT-7400 virus was lethal for rabbits, apparently without replicating to a significant extent. It was not pathogenic for adult mice inoculated intravenously or for adult or suckling mice inoculated intracerebrally and intraperitoneally. Unlike an orbivirus isolated from Culex mosquitoes in China, JKT-7400 did not interfere with the replication of Japanese encephalitis virus in mosquitoes.

[Prolonged culture of hepatocytes from healthy adult human livers; immunologic characterization of the hepatocyte nature of cultivated cells]. / Culture prolongée d'hépatocytes provenant de foies sains de sujets humains adultes; caractérisation immunologique de la nature hépatocytaire des cellules cultivées.

Monolayer cultures were obtained from human liver explants. Some cells, which extend in all directions, are trypsinized then collected by differential centrifugation and incubated at 38 degrees 5. The oldest culture is 12 months old. Albumin and alpha 1-antitrypsin are constantly detected and measured in the supernatent by radioimmunoassay. The liver specific protein is always characterized by immunofluorescent staining on the surface of the cultivated cells.

Long term cultivation of functionally active normal human adult hepatocytes.

Monolayer cultures were obtained from human liver explants. The cells, which extend in all directions, are trypsinized then collected by differential centrifugation and incubated at 38 degrees 5. The oldest culture is 12 month-old. Albumin and alpha 1-antitrypsin are constantly detected and measured in the supernatant by radioimmunoassay. The liver specific protein is always characterized by immunofluorescent staining on the surfaces of the cultivated cells.

Mouse natural autoantibodies can interfere with murine alpha and beta interferons.

Natural polyspecific autoantibodies could impede the establishment of an antiviral state by mouse alpha and beta interferons (IFN) as determined by an IFN assay with L929 cells and with vesicular stomatitis virus as the challenge virus. This anti-IFN effect was due to interactions with cell surface constituents rather than to antibody activity against IFN. This observation supports the hypothesis that natural autoantibodies participate in specific immune regulation as well as in the regulation of nonspecific host defense.

Beneficial effect of cyclosporin A on the lymphocytic choriomeningitis virus infection in mice.

The effect of cyclosporin A on the course of lymphocytic choriomeningitis virus infection in mice was investigated. Evidence is presented that administration of this immunosuppressive drug spares a majority of lethally infected mice. This beneficial effect is different from the one obtained with other treatments leading to the abolition of T cell functions. Surviving animals rapidly eliminate the virus and produce high titers of neutralizing IgG antibodies.

Lymphocytic choriomeningitis virus-induced immunodepression: inherent defect of B and T lymphocytes.

Infection of mice with lymphocytic choriomeningitis virus (LCMV) produces a rapidly induced immuno-suppression manifested by low lymphocyte proliferation in response to lipopolysaccharide (LPS) and concanavalin A (ConA). Analysis of the mechanisms underlying the unresponsiveness to these mitogens was undertaken at the cellular and molecular levels 7 days after infection. The selective elimination of CD8+ T cells and the results of coculture experiments demonstrated that unresponsiveness was not due to suppressor cells. Similarly, the role of inhibitory factors such as prostaglandins was excluded, since indomethacin, which inhibits their production, did not reverse the unresponsiveness. Analysis of different cytokines secreted by ConA-activated macrophages or T cells revealed that interleukin-1 (IL-1), synthesized during the T-dependent activation of macrophages by ConA, was normally produced by cells from LCMV-infected mice. In contrast, IL-2, which is produced by activated CD4+ T cells, was undetectable. Addition of exogenous IL-2 did not restore the proliferative response, although the p55-kilodalton protein of the IL-2 receptor was induced by ConA on CD4+ cells from LCMV-infected mice. Our results can be interpreted as showing that (i) unresponsiveness to mitogens of cells from LCMV-infected mice is not due to altered functions of the macrophages with respect to IL-1 production; (ii) CD4+ cells are activated, since the p55 chain of the IL-2 receptor is induced; (iii) the lack of IL-2 production cannot explain T-cell unresponsiveness, since addition of exogenous IL-2 did not restore the proliferative response. Taken together, these data suggest that T-lymphocyte unresponsiveness should be related to an inherent proliferative defect subsequent to T-cell activation and IL-2 receptor expression.

Anti-interferon globulin inhibits the development of glomerulonephritis in mice infected at birth with lymphocytic choriomeningitis virus.

Swiss mice infected at birth with lymphocytic choriomeningitis virus develop glomerulonephritis. Injection of potent anti-mouse interferon globulin at the time of viral infection inhibited the development of these renal lesions. We conclude that the production of endogenous interferon by this virus in the first few days of life plays an important role in the pathogenesis of this glomerulonephritis.

Inhibition by anti-interferon serum of lymphocytic choriomeningitis virus disease in suckling mice.

Inoculation of newborn mice with lymphocytic chloriomeningitis (LCM) virus resulted in decreased weight gain, liver cell necrosis, and death. Injection of potent sheep immunoglobulin against mouse interferon markedly inhibited these manifestations of LCM virus disease despite the fact that these treated mice had 100-fold more LCM virus in their serum. We conclude that interferon induced by LCM virus is responsible in large part for the syndrome of growth inhibition, liver cell necrosis, and death observed in LCM virus-infected suckling mice.

Lymphocytic choriomeningitis infection in the nude mouse. An immunopathological study.

Immunopathological studies of the kidney, determination of circulating immune complexes and interferon blood levels were obtained in adult congenitally-athymic nude mice ((nu/nu) infected with lymphocyte choriomeningitis (LCM) virus as well as in their phenotypically-normal litter mates (nu/+). As previously reported, intracerebral or intraperitoneal infection in nu/nu mice did not induce any mortality and resulted in a carrier state characterized by persistently high levels of virus in the circulation. Interferon was present in the circulation for approximately 6 days. Circulating immune complexes were not detectable and glomerulonephritis assessed by light microscopy, electron microscopy and immunofluorescence, was either absent or very mild. These observations show that although a carrier state can be induced in adult nude mice, circulating immune complexes and glomerulonephritis do not develop. This situation is markedly different from that induced in normal Swiss mice infected at birth, which is characterized by raised levels of circulating immune complexes and development of glomerulonephritis in all infected mice.