Lymphocytic Choriomeningitis Virus Infection In Mice Research Articles

High frequency of T lymphocytes committed to interferon-gamma transcription upon polyclonal activation in spleen from lymphocytic choriomeningitis virus-infected mice.

Splenic T lymphocytes from C3H/HeOur mice infected for 7 days with lymphocytic choriomeningitis virus (LCMV) do not proliferate in response to concanavalin A (Con A). Although the IL-2 gene remained silent after polyclonal activation, the gene encoding the p55 chain of the IL-2 receptor was normally transcribed. These data indicated that the co-ordinated expression of the unique wave of cytokine and cytokine receptor expression, associated with T cell triggering, did not occur in T lymphocytes from LCMV-infected mice. In a first attempt to characterize the potential of these cells to initiate the transcription of cytokine genes, we have focused our attention on interferon (IFN)-gamma, a cytokine displaying multifocal activities on the immune response. We found that the IFN-gamma encoding gene, silent before Con A activation, was transcribed after triggering in normal and LCMV-infected cells. Notably, the level of induction was approximately 10-fold higher in LCMV mice than in non-infected control mice. IFN-gamma gene was induced in both CD4 and CD8 subsets. Induction was sensitive to cycloheximide addition and thus required de novo protein synthesis. The high level of IFN-gamma mRNA transcripts was correlated with a high frequency of cells transcribing this gene. By in situ hybridization we showed that the majority (approximately 70%) of the splenic T lymphocyte population were positive for IFN-gamma mRNAs. A matching increase in IFN-gamma protein corresponded to this elevated IFN-gamma mRNA level. This observation revealed the existence in LCMV-infected mice of a preponderant peripheral T lymphocyte population which displayed unusual activation and proliferative characteristics.

Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the beta 2-microglobulin gene.

Mice infected intracerebrally with lymphocytic choriomeningitis virus (LCM virus) develop a characteristic central nervous system disease and usually die. If the intravenous or intraperitoneal route is used, the infection leads to less severe clinical signs and the virus is eliminated. Illness and virus clearance are immunological phenomena, which are assumed to be caused exclusively by CD8+ T lymphocytes. In contrast, of the two phases of a delayed-type hypersensitivity reaction caused by inoculation of the virus into the mouse's foot, only the first is mediated by CD8+ cells, whereas the second is mediated by CD4+ cells. We have examined LCM virus-specific immune responses in mice devoid of CD8+ T lymphocytes as a result of disruption of the beta 2-microglobulin gene. As expected, the virus persisted but footpad swelling did not occur, although intracerebral infection resulted in CD4+ T-lymphocyte-mediated illness and antiviral antibodies were produced. Different results had been obtained by Fung-Leung et al. (W.-P. Fung-Leung, T. M. Kündig, R. M. Zinkernagel, and T. W. Mak, J. Exp. Med. 174:1425-1429, 1991), who, is essentially identical experiments but with mice lacking CD8+ T lymphocytes as a result of disruption of the Lyt-2-encoding gene, recorded control of the infection and development of a local delayed-type hypersensitivity reaction. We consider these differences important, because they provide us with clues that may help to understand the mode of action of the CD8+ T cells in cell-mediated antiviral immunity.

Virus-triggered AIDS: a T-cell-mediated immunopathology?

Based on the characteristics of lymphocytic choriomeningitis virus (LCMV) infection of mice, Rolf Zinkernagel proposes here that virus-triggered acquired immune deficiency disease (AIDS) may be at least partially caused by a T-cell-mediated immunopathalogy in which virus-specific cytotoxic T cells destroy virus-infected cells that are involved in immune responses. Thus, one part of the immune system destroys another essential component because it is virally infected. During LCMV infection in mice - and by extrapolation HIV infection in humans - elimination of cytotoxic T (CD8 +) cells, or the generation of CD8 + T-cell tolerance to the virus, may lead to a symptom-free virus-carrier state.

Viral infection of neurons can depress neurotransmitter mRNA levels without histologic injury

Neonatal mice inoculated with lymphocytic choriomeningitis virus (LCMV) have non-lytic persistent neuronal infection and disturbed behavior. We now show that LCMV replicates in neurons containing the neurotransmitter somatostatin without morphologic evidence of injury and that persistent neuronal LCMV infection in mice is attended by a decrease in brain levels of somatostatin mRNA. Brain levels of mRNA for another neurotransmitter peptide, cholecystokinin, are not decreased. These data are the first to localize a virus to a specific neurotransmitter-containing cell during in vivo infection and suggest that persistent viral infections could cause neurologic or psychiatric diseases through selective effects brain levels of neurotransmitter mRNAs.

Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response.

After intravenous infection of mice, lymphocytic choriomeningitis virus multiplied in spleens and livers, attaining highest concentrations on days 4 to 6. The subsequent clearance was as rapid, and 8 to 10 days after inoculation, infectivity was usually below detectability. During the effector phase of virus elimination, both cytotoxic T-cell (CTL) activity and the number of cells producing antiviral antibodies were high. Monoclonal antibodies directed against T lymphocytes and T-lymphocyte subsets were inoculated once intravenously 5, 6, or 7 days after infection of the animals, and the effects on antiviral immune responses, as well as on elimination of virus from the organs, were determined. Treatment with anti-Thy-1 and anti-Lyt-2 antibodies blocked elimination of the virus and profoundly diminished the activity of spleen CTLs but reduced the antibody response partially (anti-Thy-1) or increased it (anti-Lyt-2). In contrast, treatment with the anti-L3T4 antibody had essentially no effect on either virus elimination or CTL response but abolished antibody production. We conclude that Lyt-2+ (cytotoxic-suppressive) T lymphocytes are needed for elimination of the virus and also regulate the humoral response but that antiviral antibodies are not essential for control of the infection.

Prévention par les globulines anti-interféron de la mortalité des souris infectées par le virus de la chorioméningite lymphocytaire: Prevention of death in mice fatally infected with lymphocytic choriomeningitis virus by anti-interferon globulins

Intracerebral inoculation of adult mice with lymphocytic choriomeningitis (LCM) virus is lethal, and is considered to be due to the development of sensitized T lymphocytes which are cytotoxic for virus-infected host cells. Injection of sheep anti-mouse interferon globulin into LCM virus-infected mice resulted in a 100 to 1,000-fold increase in viral titres, a 10 to 100-fold increase in serum interferon titres and the survival of virtually all of the mice. Anti-interferon globulin-treated mice also showed a focal necrosis of spleen and lymph nodes and a depletion of thymic lymphocytes. These lesions were more marked than in the organs of LCM virus-infected mice injected with normal sheep serum. The increased amounts of virus and/or interferon in mice injected with anti-interferon globulin and the marked lesions in these lymphoid organs may depress the immune response and thus be related to the survival of virus infected mice. L'inoculation intracérébrale du virus de la chorioméningite lymphocytaire (CML) à des souris adultes entraîne la mort, qui est due à une réaction immunitaire spécifique à lymphocytes T cytotoxiques dirigés contre les cellules infectées de l'hôte. Afin de dégager le rôle que pouvait jouer l'interféron au cours de cette infection, nous avons traité les animaux infectés par des globulines de mouton anti-interféron de souris (GAIF). Dans ces conditions, les souris survivent à l'infection cérébrale. Elles ont des lésions de nécrose de la rate et des ganglions ainsi qu'une aplasie du thymus beaucoup plus intenses et plus durables que celles des souris témoins infectées et traitées par des globulines de mouton normal (GMN). Chez les animaux traités par les GAIF et infectés avec de faibles ou de fortes doses de virus, le virus est présent plus tôt et à des titres cent à mille fois plus élevés que chez les témoins. Le taux d'interféron circulant est également dix à cent fois plus élevé chez ces animaux. Les lésions de la rate et des ganglions apparaissent en même temps que l'interféron et sont d'autant plus intenses que la production d'interféron et de virus est élevée. Le virus et/ou l'interféron pourraient être responsables de ces lésions qui seraient à l'origine d'une immunodépression diminuant ou empêchant la réaction immunitaire dans les méninges, d'où une survie des souris infectées.

Effector T lymphocytes in lymphocytic choriomeningitis virus-infected mice. Cytolytic activity of Lyt-23 spleen cells in vitro does not correlate with elimination of infectious virus from spleens.

The T lymphocytes from mice recovering from infection with lymphocytic choriomeningitis virus were selected for subclasses by treatment with anti-Lyt antisera and complement. Lyt-23 cells and mixtures of lyt-1 and Lyt-23 cells caused up to one-half the destruction of cultivated target cells as compared with untreated T lymphocytes; Lyt-1 cells alone were not cytotoxic. Selected and unselected spleen T cells were also inoculated intravenously into previously infected mice. Whereas unselected cells reduced infectious virus in the spleens of the recipients approximately 100-fold, only marginal effects, which were not preferentially associated with one particular subclass, were seen with selected LYT-23 or Lyt-1 lymphocytes or a mixture of both. Apparently the Lyt-23 cells, shown to by cytolytic for infected cells in vitro, did not cause elimination of a measurable quantity of the virus from mice.

Changes in Hemopoiesis During the Course of Acute LCM Virus Infection in Mice

Although severe hematologic and immunologic disorders occur in several viral infections, insight into the mechanisms by which viruses may affect hemopoietic tissues is poor. The previous demonstration of distinct immunohemopoietic lesions in mice with acute lymphocytic choriomeningitis (LCM) virus infection has led us to investigate the function of hemopoietic precursor cells in the course of this experimental infection. During the first week of infection, there was profound suppression of pluripotential stem cell (CFU) and in vitro colony-forming cell (CFU) compartments, and of 59Fe uptake into hemopoietic tissues. During the same period, we found enhanced activity of colony-stimulating factor, lack of responsiveness to erythropoietin, and appreciable titers of interferon in blood and spleen. After day 10 post infection, there was a striking increase in CFU and 59Fe uptake confined to spleen and blood. Restoration of bone marrow, however, was markedly delayed. With reference to recent studies on interferon, and the findings in mice with persistent LCM virus infection, we suggest that interferon may be the comprehensive suppressor of the hemopoietic precursor cells in the first stage of acute LCM virus infection, and that these cells in the recovery period are directed preferentially into erythropoiesis.

Changes in hemopoiesis during the course of acute LCM virus infection in mice

Although severe hematologic and immunologic disorders occur in several viral infections, insight into the mechanisms by which viruses may affect hemopoietic tissues is poor. The previous demonstration of distinct immunohemopoietic lesions in mice with acute lymphocytic choriomeningitis (LCM) virus infection has led us to investigate the function of hemopoietic precursor cells in the course of this experimental infection. During the first week of infection, there was profound suppression of pluripotential stem cell (CFU) and in vitro colony-forming cell (CFU) compartments, and of 59Fe uptake into hemopoietic tissues. During the same period, we found enhanced activity of colony-stimulating factor, lack of responsiveness to erythropoietin, and appreciable titers of interferon in blood and spleen. After day 10 post infection, there was a striking increase in CFU and 59Fe uptake confined to spleen and blood. Restoration of bone marrow, however, was markedly delayed. With reference to recent studies on interferon, and the findings in mice with persistent LCM virus infection, we suggest that interferon may be the comprehensive suppressor of the hemopoietic precursor cells in the first stage of acute LCM virus infection, and that these cells in the recovery period are directed preferentially into erythropoiesis.

Transient impaired cell-mediated tumor immunity after acute infection with lymphocytic choriomeningitis virus.

Intraperitoneal injection of nononcogenic lymphocytic choriomeningitis (LCM) virus in adult C3H mice causes a symptomless infection but stimulates specific cell-mediated and humoral immune responses. However, median survival time of virus-infected mice inoculated with syngeneic tumor cells was significantly shortened, and growth of semiallogeneic tumors was significantly enhanced. Cell-mediated cytotoxicity measured as chromium-51 release from labeled tumor cells was significantly suppressed but was recovered within 55 days after infection. The suppressed immune responsiveness could be conferreo on a normal spleen cell population when activated in virus-infected recipients. Chronically LCM virus-infected mice showed an unimpaired cell-mediated immune response to tumor allografts.