lipid-a and Cytomegalovirus-Infections

The immunomodulating and murine cytomegalovirus (MCMV)-inhibiting effects of the synthetic lipid A subunit analogue GLA-60 were investigated in different strains of immunodeficient mice. Peritoneal natural killer (NK) cells obtained from nude (nu/nu) C57BL/6 mice or normal NMRI mice, which had been treated intraperitoneally with 10 micrograms of GLA-60 1 day earlier, exhibited a greater cytolytic activity than those from untreated mice. GLA-60 also stimulated NK cell activity in SCID (severe combined immune deficiency) mice (which are T and B cell-defective), but not in NK cell-defective beige (C57BL/6 bg/bg) mice. GLA-60 also enhanced the phagocytic activity of peritoneal macrophages in beige, nude and NMRI mice, but not in SCID mice. GLA-60, when administered as a single 150 micrograms dose 1 day before infection, completely protected beige mice against MCMV-associated mortality. It also caused a significant increase in the life-span of MCMV-infected nude and SCID mice.

Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Killer Cells, Natural; Lipid A; Macrophages; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Nude; Mice, SCID; Phagocytosis; Species Specificity

A chemically synthesized lipid A subunit analogue, GLA-60 (2-deoxy-4-O-phosphono-2-[(3R)-3-hydroxytetradecanamido]-3-O-[(3R) - 3-tetradecanoyloxytetradecanoyl]-D-glucose), has many of the activities of endotoxins but little, if any, toxicity. We investigated the protective activity of GLA-60 against murine cytomegalovirus (MCMV) infection in NMRI mice. Intraperitoneal administration of GLA-60 at 1 day before MCMV infection at doses of 1, 10, or 100 micrograms per mouse significantly reduced mortality. GLA-60 stimulated peritoneal natural killer (NK) cell and macrophage activities, and these activities were abolished by in vitro treatment with anti-asialo GM1 antibody and anti-Mac1 antibody, respectively. GLA-60 proved also protective against MCMV infection in mice in which either NK cells or macrophages were depleted by in vivo treatment with anti-asialo GM1 or anti-Mac1 antibody. The anti-MCMV activity of GLA-60 can at least be partially attributed to activation of NK cells and macrophages.

Topics: Adjuvants, Immunologic; Animals; Cytomegalovirus Infections; Female; G(M1) Ganglioside; Injections, Intraperitoneal; Killer Cells, Natural; Lipid A; Macrophage Activation; Macrophage-1 Antigen; Mice; Phagocytosis