Nitric Oxide Inhibits Marek's Disease Virus Replication but Is Not the Single Decisive Factor in Interferon-γ-Mediated Viral Inhibition

Abstract

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.

Cytokines Evaluation of Different Mareks Disease Virus Vaccines in Broiler Chickens

“…For example, Djeraba and co-workers reported an increased IFN-γ mRNA expression in the splenocytes of vaccinated bird with CVI-988 strain and challenged with very virulent MDV, RB-1B strain (A Djeraba et al, 2000). In parallel, Abdulcareem et al, (2008) have reported an increased expression of IFN-γ gene in feather tips of CVI988 and HVT vaccinated chickens by 10 days PI (M F Abdul-Careem et al, 2008).…”

“…IFN-γ has been reported to inhibit MDV replication by activating macrophages to initiate cell mediated cytotoxicity for MDV-infected cells (Lee, 1979;Djeraba et al, 2000;Djeraba et al, 2002). Furthermore, IFN-γ directly activates CD8+ CTLs to kill the virally-infected cells (Whitmire et al, 2005).…”

“…Cytokines as the secreted products of CTLs are proposed to play key roles against MDV infection, shaping the viral pathogenesis (Xing & Schat, 2000) and may possess protective responses following vaccination (Djeraba et al 2000;Kano et al 2009). In spite of, the fact that MDV was the first oncogenic virus to which vaccines were available (Baigent et al 2006), the virus is continually evolving toward greater virulence impacting those vaccines efficacy.…”

Th1 and Th2 Cytokines Activity during Transformation and Lymphoma Formation Stage in Chicken Naturally Infected with Marek's disease virus.

“…IFN-γ expression is inversely proportional to IL-10 production, as IL-10 inhibits IFN-γ production in chickens (Rothwell et al, 2004). So it is logically to found lower expression of IFN-γ and progressive lymphoma formation due to MDV, as the main function of IFN-γ as antiviral activity (Djeraba et al, 2000;Lee, 1979;Xing and Schat, 2000a) was inhibited by over production of IL-10 produced by regulatory T cells.…”

Evaluation system for an experimental study of low-pathogenic avian influenza virus (H9N2) infection in specific pathogen free chickens using lactic acid bacteria,Lactobacillus plantarumKFCC11389P

“…NO is also a potent antiviral agent, and several papers have suggested that NO might play an important role during virus infection (Djerabe et al, 2000;Xing & Schat, 2000;Koci et al, 2004). In contrast, several studies in mouse models demonstrated that overproduction of free radicals, such as NO, contributed to development of pneumonia during influenza virus infection and caused pulmonary damage (Akaike et al, 1996;Kačergius et al, 2006).…”