cord-factors and Orthomyxoviridae-Infections

Normal mice inoculated intravenously with 50 microg trehalose-6,6'-dimycolate, a glycolipid component of the cell wall of Mycobacterium, in an oil-in-water emulsion (TDM emulsion) acquired a high resistance to intranasal lethal infection of an influenza virus. In contrast, TDM emulsion-treated T-cell receptor delta gene mutant (TCR delta-/-) mice acquired insufficient resistance against the lethal influenza virus infection. The patterns of insufficient resistance were identical to the results obtained previously with mice which were depleted of T-lymphocytes bearing gammadelta T-cell receptors (gammadelta T-cells) by in vivo administration of anti-gammadelta T-cell receptor monoclonal antibody (Hoq et al, J. Gen. Virol. 78: 1597-1603, 1997). These results strongly suggest that the gammadelta T-cells play an important non-specific role in resistance against influenza virus infection.

Topics: Animals; Cord Factors; Emulsions; Female; Genes, T-Cell Receptor delta; Immunity, Innate; Influenza A virus; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Mycobacterium tuberculosis; Orthomyxoviridae Infections; Species Specificity; Specific Pathogen-Free Organisms

Cyclosporin A (CsA), which is an immunosuppressive drug of helper T lymphocytes, diminished a resistance of mice to influenza virus infection. Mice inoculated intravenously with trehalose-6,6'-dimycolate (TDM, a glycolipid component of the cell wall of Mycobacterium) in an oil-in-water emulsion (TDM emulsion) recovered the resistance to influenza virus infection impaired by CsA. Number of antibody-producing cells was markedly reduced in CsA- and/or TDM-treated mice. Interferon production in lung of TDM-treated mice was augmented; however, it was extremely reduced not only in CsA-treated mice, but also in CsA- and TDM-treated mice. Activities of natural killer cells of CsA- and/or TDM-treated mice were not different from that of control mice. Numbers of lymphocytes in lung of TDM-treated mice and CsA- and TDM-treated mice were more predominantly increased than that of control mice. Analysis of lung lymphocytes by flow cytometry revealed no difference between the populations of L3T4+ T lymphocytes and Lyt-2.2+ T lymphocytes in CsA- and/or TDM-treated mice and the populations in control mice. However, the population of gamma delta T cell receptor positive (gamma delta TCR+) lymphocytes increased markedly in lung of TDM-treated mice and also CsA- and TDM-treated mice. In vitro experiments showed that macrophage cultures treated with TDM emulsion released a mediator(s) which activates T lymphocytes, but not B lymphocytes. These and our earlier results suggest that the recovered anti-influenza virus resistance of CsA-treated mice by treatment with TDM emulsion was caused by elicitation of macrophages with TDM, then activation of T lymphocytes, especially gamma delta TCR+ lymphocytes.

Topics: Animals; Antibodies, Viral; Antibody-Producing Cells; Cells, Cultured; Cord Factors; Cyclosporine; Female; Immunity, Innate; Influenza A virus; Injections, Intravenous; Interferons; Killer Cells, Natural; Lung; Lymphocyte Activation; Lymphocyte Subsets; Macrophages; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections

Mice inoculated intravenously with trehalose-6,6'-dimycolate (TDM), a glycolipid component of the cell wall of Mycobacterium, in an oil-in-water emulsion (TDM emulsion) acquired a high resistance to intranasal infection by influenza virus. Athymic nude mice inoculated with TDM emulsion could not acquire such an augmented resistance to influenza virus infection. The augmented antiviral resistance of TDM emulsion-treated mice was diminished by prior intravenous inoculation of silica particles, which selectively impair macrophage functions. In vitro experiments showed that macrophage cultures treated with TDM emulsion released an activator(s) of T lymphocytes. Histological studies of the lung of TDM emulsion-inoculated mice revealed that a typical granuloma and severe perivascular lymphocyte infiltration appeared, though no such histological change was observed in the lung of control emulsion-inoculated mice. The lungs from TDM emulsion-treated athymic nude mice and the lungs from silica particle- and TDM emulsion-treated mice showed fewer and smaller granulomata and milder perivascular lymphocyte infiltration than a typical granuloma and lymphocyte infiltration in the lungs of TDM emulsion-treated mice. These and earlier results suggest that an acquired antiviral resistance of TDM emulsion-treated mice was caused by elicitation of macrophages with TDM, then activation of T lymphocytes, leading to granuloma formation and an amplified earlier interferon production in response to influenza virus infection.

Topics: Animals; Cells, Cultured; Cord Factors; Emulsions; Female; Glycolipids; Immunity, Innate; Influenza A virus; Interferons; Lung; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, Nude; Orthomyxoviridae Infections; T-Lymphocytes

Mice inoculated intravenously with 10 to 100 micrograms trehalose-6,6'-dimycolate in an oil-in-water emulsion (TDM emulsion) acquired high resistance to intranasal infection by influenza virus at 7 to 14 days, but not at 1 day, after treatment. Mice inoculated with an oil-in-water emulsion without TDM (control emulsion) did not resist infection. The activity of the reticuloendothelial system of mice inoculated with TDM emulsion or control emulsion was greatly stimulated 1 day and 14 days after treatment. Interferon production in response to influenza virus was augmented in lung and serum of TDM emulsion-treated mice. The augmented interferon production was greatly diminished in the TDM emulsion-treated mice by treatment with anti-Thy-1.2 monoclonal antibody. Production of haemagglutination-inhibiting antibody in the TDM emulsion-treated or control emulsion-treated mice was higher than that in untreated mice, although no difference was observed between the TDM emulsion-treated and control emulsion-treated mice. On the other hand, TDM emulsion treatment of mice did not influence the appearance of antibody-producing cells, nor the activity of natural killer cells in the mice. The enhanced resistance of mice was diminished by inoculating anti-interferon-alpha/beta serum before influenza virus infection. No detectable interferon activity was observed in lung and blood of mice inoculated with anti-interferon-alpha/beta serum prior to influenza virus infection. These results suggest that the augmented early interferon production in T-lymphocytes of TDM emulsion-treated mice in response to influenza virus may play an important role in the enhanced resistance.

Topics: Animals; Antibodies, Monoclonal; Cord Factors; Female; Glycolipids; Immunity, Active; Influenza A virus; Interferon Inducers; Interferon Type I; Mice; Mice, Inbred Strains; Orthomyxoviridae Infections; T-Lymphocytes

The ability of nontoxic monophosphoryl lipid A (MPL) to stimulate nonspecific resistance against viral infection was investigated. Mice pretreated intravenously with squalane-in-water emulsions of MPL, alone or in combination with other immunostimulants, were given an aerosol of influenza virus three weeks after the pretreatment. Complete protection against lethal influenza virus infection was conferred when MPL was combined with trehalose dimycolate (TDM). The protective activity of MPL plus TDM combination was corroborated by a significant reduction of the lung virus titers. Combination of lower doses of MPL with TDM extracted from Mycobacterium bovis, but not with that of M. phlei, induced significant resistance to influenza virus. Preparations containing MPL alone, or combined with mycobacterial cell wall skeleton or muramyl dipeptide, were not effective. The adjuvant activity of MPL on bivalent influenza subunit vaccine was also studied. The primary antibody responses to influenza A and influenza B antigens were enhanced by the addition of MPL and were higher than the vaccine associated with aluminum hydroxide. The adjuvant activity of MPL was confirmed by the elevated secondary response. High levels of circulating antibodies were still present in the MPL group when antibody titers in the controls were waning.

Topics: Adjuvants, Immunologic; Animals; Chick Embryo; Cord Factors; Drug Interactions; Female; Glycolipids; Immunity, Innate; Influenza A virus; Lipid A; Mice; Mice, Inbred Strains; Mycobacterium; Orthomyxoviridae Infections; Salmonella

The effect on respiratory burst of splenic cells from mice pretreated with oil-in-water emulsions of muramyl dipeptide (MDP), trehalose dimycolate (TDM), or the combination of MDP with TDM was studied by luminol-dependent chemiluminescence in response to stimulation by zymosan. Spleen cells from mice pretreated with TDM, but not those of mice treated with MDP, generated increased chemiluminescence. Spleen cells from animals pretreated with the combination of MDP and TDM exhibited markedly enhanced chemiluminescence activity. The effect of enhanced activity of preparations containing MDP combined with TDM was further examined in vivo by an aerosol infection of pretreated mice with a mouse-pathogenic influenza virus. Pretreatment with 6-O-acyl analogs and one ubiquinone derivative of MDP alone did not induce any resistance against influenza virus. Significant protection was conferred only when MDP and certain analogs were combined with TDM. The enhancement of nonspecific resistance to influenza virus infection was related to the chemical structure of the synthetic immunostimulant. A greater degree of protection was induced by the combination of TDM with the lipophilic derivatives like B 30-MDP and L-18 MDP.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Cord Factors; Glycolipids; Immunity, Innate; Influenza A virus; Luminescent Measurements; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Orthomyxoviridae Infections

The effects of two aminobutyryl and four seryl analogs of the synthetic muramyl dipeptide (MDP) against aerosol infections with influenza virus and Mycobacterium tuberculosis were studied. Regardless of the MDP analog employed, there was no evidence that the resistance against viral and bacterial aerosol infections was enhanced in the treated mice. In parallel studies, significant protection against influenza virus and M. tuberculosis infections was induced by the combination of MDP or analogs with the mycobacterial glycolipid trehalose dimycolate (TDM). Resistance conferred by the MDP + TDM combination against influenza virus was present 1 week after pretreatment and could be abrogated by macrophage inhibitory agents silica, dextran sulfate, and carrageenan. Splenic cells from MDP + TDM-pretreated animals generated markedly enhanced levels of luminol-dependent chemiluminescence in response to influenza A and B viruses.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Cord Factors; Glycolipids; Immunity, Innate; Macrophages; Mice; Mice, Inbred BALB C; Mycobacterium Infections; Mycobacterium tuberculosis; Orthomyxoviridae Infections; Spleen; Structure-Activity Relationship