Infection of SCID mice with lactate dehydrogenase-elevating virus stimulates B-cell activation.

Mice of the C.B-17 strain homozygous for the scid mutation (SCID mice) were infected with lactate dehydrogenase-elevating virus (LDV), and plasma samples obtained at intervals up to 42 days postinfection were analyzed for total immunoglobulins, anti-LDV antibodies, virus-specific immune complexes, and viremia levels. The mice responded to LDV infection with transient increases in total blood IgM, production of IgM-antigen complexes and IgM anti-LDV, as well as increased blood IgG2a. However, SCID mice failed to make a specific IgG2a anti-LDV immune response, and their blood LDV levels were elevated about 100-fold relative to those of control mice. The results suggest a role for IgG antibodies in the regulation of viremia and demonstrate a viral pathway of B-cell differentiation in SCID mice.

Cytokine regulation of lactate dehydrogenase-elevating virus: inhibition of viral replication by interferon-gamma.

The mechanisms which regulate the replication of lactate dehydrogenase-elevating virus (LDV), a persistent murine model virus which infects macrophages, are unclear. For this study, the effects of murine recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on LDV replication were examined. LDV permissiveness was reduced in macrophages obtained from uninfected mice treated with IFN-gamma prior to cell harvest and in vitro LDV infection. Virus inhibition by IFN-gamma was also observed when neonatal LDV-infected mice were injected with this cytokine prior to macrophage harvest and analysis of LDV replication-positive cells. Persistently LDV-infected mice demonstrated an increase in viremia levels following treatment with TNF-alpha. Neither IFN-gamma nor TNF-alpha had any direct in vitro effect on LDV replication in cultured macrophages, suggesting that the actions of these cytokines required secondary or accessory in vivo events. These results provide evidence for cytokine-mediated regulation of LDV infection and support a role for the immune system in the LDV-host relationship.

Enhancement of murine susceptibility to oral lactate dehydrogenase-elevating virus infection by non-steroidal anti-inflammatory agents, and antagonism by misoprostol.

The murine lactate dehydrogenase-elevating virus (LDV) was used to study the effects of prostaglandin-acting agents on mucosal resistance to virus infection. Mice treated with non-steroidal anti-inflammatory drugs (NSAIDs) prior to oral exposure to LDV demonstrated a reduction in the mucosal barrier to LDV infection. Histological studies indicated that these NSAID effects were not a result of gross or microscopic tissue damage. The effects of two NSAIDs, indomethacin and diclofenac, were inhibited by co-treatment of mice with misoprostol, a synthetic PGE1 analog. The ability of misoprostol to modulate NSAID effects was not due to direct antiviral activity or to actions on LDV-permissive macrophages. These results show that the mammalian mucosal barrier to virus infection is prostaglandin-sensitive, and provide a model for the study of resistance to viral infection.

Virucidal effect of murine duodenal extracts: studies with lactate dehydrogenase-elevating virus.

Mucosal resistance to infection with lactate dehydrogenase-elevating virus (LDV) has been previously demonstrated, and the LDV system presents an important murine model for the study of mucosal barriers to viral infection. In the present study, duodenal molecules were isolated from normal mice which had potent virucidal activity, when tested against LDV as well as canine herpes, canine hepatitis, Semliki forest, and visna viruses. The virucidal activity was demonstrated to be non-immune in nature, and was present in apparently non-enzymatic protein molecules, having a molecular mass of between 10-100 kDa by membrane filtration and 10-17 kDa by gel filtration. The anti-LDV activity of these molecules was suppressed by anti-duodenum antibodies in vitro, and in vivo studies suggested a possible protective role for the anti-viral molecules. We conclude that the normal mouse duodenum contains potent virucidal molecules, which are of interest to the study of biological and molecular mechanisms of viral resistance.

Immunoglobulin transfer from immune-reconstituted SCID mice to nursing neonates: blood distribution of antibody and association with perinatal virus protection.

Previous work in our laboratory has shown that fetal protection from maternal transmission of the murine lactate dehydrogenase-elevating virus (LDV) infection is mediated by adoptive transfer of maternal anti-viral immunity. In the present report, we have characterized reconstitution of immunity in immunodeficient SCID mice following transplantation with BALB/c spleen cells, and studied the fate and distribution of maternally-derived antibodies after passage to neonatal SCID mice by nursing. Immune-reconstituted SCID mice maintained stable immunity for up to 7 months post-transplantation, during which time they produced nonneutralizing IgG anti-LDV antibodies and protected their offspring from maternally-derived LDV infection. Using IgG isotype and allotype assays, it was found that maternal IgG antibodies transferred from breast milk to nursing neonatal mice and appeared in their circulation. Weaning of SCID mice from immunocompetent mothers permitted the determination of blood immunoglobulin isotype half-lives (3.6-10.6 days) in the absence of endogenous antibody production. LDV infection was transferred to nursing mice by nonimmune LDV-infected mothers, but protection from nursing-acquired LDV infection was associated with maternal viral immunity, breast milk transfer of IgG anti-LDV to nursing mice, and reduced breast milk virus titers. These findings show a nursing pathway for LDV infection, and demonstrate the potential of immune protection from this infection pathway.