Intravenous treatment with liposome-encapsulated dichloromethylene bisphosphonate (C12MBP)suppresses nitric oxide production and reduces genetic resistance to Marek's disease

Abstract

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.

Role of Macrophages in the Pathogenesis of Genotype VII Newcastle Disease Virus in Chickens

“…NDV infection after macrophage depletion enhanced splenic pathology, which may be also related to the impaired capability to clear apoptotic and necrotic cells induced by virus infection due to the decreased amount of macrophages. These findings were consistent with the results for many other pathogens, including measles virus, H3N2 influenza virus, MERS-CoV and MDV [ 27 , 28 , 29 , 30 ]. Therefore, macrophages function to protect against NDV-mediated pathology.…”

“…Similarly, the depletion of macrophages from the lungs via intranasal inoculation of CL lipo did not affect the replication of Middle East respiratory syndrome coronavirus (MERS-CoV) in mice [ 27 ]. In contrast, the replication of Marek’s disease virus (MDV) and H3N2 influenza virus in the host was significantly increased after CL lipo treatment [ 28 , 29 ]. The findings obtained in our study seem to be conflicting with the high infectivity of NDV in macrophages.…”

Low pathogenic avian influenza virus infection increases the staining intensity of KUL01+ cells including macrophages yet decrease of the staining intensity of KUL01+ cells using clodronate liposomes did not affect the viral genome loads in chickens

“…The effect of depletion of macrophages using clodronate liposomes has been studied against various virus infections in mouse models, such as measles (Roscic-Mrkic et al, 2001) and influenza (Tate et al, 2010). In chickens, increased Marek's disease virus genome load in the blood and spleen following treatment with clodronate liposomes has been shown (Rivas et al, 2003). However, macrophage depletion using clodronate liposomes has not been extensively studied during other viral infections in chickens.…”

Herpesviridae - A Look Into This Unique Family of Viruses

“…Macrophages are also able to produce large quantities of Nitric Oxide (NO) (Hussain & Qureshi, 1997); depletion of these cells causes the suppression of NO production and so the increase of viral load in the blood, tumour incidence and tumour load (Rivas et al, 2003). Moreover, in addition the high levels of IL-1, IL-6, IL-12, iNOS, and type 1 and 2 IFNs, the relative expression levels of IL-4, IL-10, and IL-13 were significantly upregulated in the infected chickens during the lytic phase of infection compared to uninfected controls.…”