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The purpose of this study was to determine to what extent nitric oxide (NO) may play a role in the antiviral-mediated effect of chicken IFN-gamma against the Marek's disease virus (MDV) RB-1B. NO-generating compounds S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholino-sydononimine (SIN-1) strongly inhibited RB-1B replication in chicken embryo fibroblasts (85%) in a dose-dependent manner. The addition of superoxide dismutase (SOD) did not alter the inhibitory effect of SIN-1, which is also known to generate superoxide anions. IFN-gamma-stimulated embryo fibroblasts almost totally suppressed viral replication and were high NO producers. Nevertheless, addition of N(G)-monomethyl-l-arginine (l-NMMA), a competitive inhibitor of NO synthase, inhibited NO production without preventing the dramatic viral suppression. IFN-gamma-stimulated chicken bone-marrow macrophages were good NO producers and demonstrated a specific cell dose-related inhibiting effect on RB-1B replication in bystander fibroblasts (around 60% at 10(6) macrophages). Adding l-NMMA together with oxygen scavengers such as SOD or d-mannitol restored viral replication almost completely. In conclusion, NO alone is a powerful inhibitor of MDV replication in chicken fibroblasts. Nevertheless, NO is not responsible for the direct inhibitory effect of the IFN-gamma treatment of fibroblasts and is only partially involved in the inhibitory effect of IFN-gamma-stimulated macrophages, which is also mediated by reactive oxygen intermediates.

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In this study the functional effectiveness of in vivo macrophage depletion using liposome-encapsulated dichloromethylene bisphosphonate (Cl(2)MBP) was examined in the chicken. The main target organs for systemic liposome-encapsulated Cl(2)MBP treatment are the spleen and the liver. Intravenous treatment with Cl(2)MBP of B(21)/B(21) chickens, genetically resistant to Marek's disease (MD), before challenge with the very virulent strain RB-1B, increased viral load in the blood and spleen after the first week and up to 6 weeks post-infection. In addition, Cl(2)MBP treatment dramatically increased tumour incidence and tumour load, especially in the spleens and livers of sick animals, but without affecting MD-specific mortality of B(21)/B(21) chickens infected with RB-1B at 12 days of age. Nitric oxide (NO) is an important effector of the macrophage and has antiviral and antitumoural properties. NO has been shown to be one of the mechanisms triggered in resistance to Marek's disease. Intravenous treatment with Cl(2)MBP before infection with RB-1B induced a long-lasting decrease in numbers of macrophages and reduction in splenic inducible NO production associated with an absence of nitrate induction in the serum (up to 6 weeks p.i.). These results do not identify macrophage and NO production as major effector components in genetic resistance to Marek's disease, but underline their roles in limiting viraemia and tumour development in organs such as the spleen and the liver.