Antiviral Activity Of Macrophages Research Articles

Block of Death-Receptor Apoptosis Protects Mouse Cytomegalovirus from Macrophages and Is a Determinant of Virulence in Immunodeficient Hosts

The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC−/−), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system.

Measurement of interferon-mediated antiviral activity of macrophages.

Macrophages have been shown to produce interferons (IFNs) that exert an antiviral effect--resistance to the cytopathic effect (CPE) of viral infection--on sensitive cell types such as fibroblasts. In some cases, IFN levels in macrophage supernatants may be below the limits of detection but still may be sufficient to confer antiviral activity on macrophages. This unit provides an assay for the qualitative demonstration of the presence or absence of endogenous IFN production in murine macrophages by measuring the resistance of macrophages to the CPE of infection with vesicular stomatitis virus (VSV).

Role of Exogenous Interferons on Intrinsic Antiviral Activity of Macrophages from Patients Affected by Neoplasia

Macrophages derived from in vitro cultured monocytes were infected with herpes simplex virus type 2. A marked impairment in the intrinsic antiviral activity was found in macrophages obtained from patients with breast cancer or melanoma. Moreover, the antiviral activity of macrophages from healthy donors, differentiated in serum from patients with neoplasia, was also impaired. The aim of this work was the evaluation of alpha, beta, gamma exogenous interferon in restoring the intrinsic antiviral activity of macrophages from patients affected by breast cancer or melanoma under different conditions. Pretreatment of macrophages with alpha, beta interferons, but not gamma interferon, restored their impaired intrinsic antiviral activity.

Role of interferon, antibodies and macrophages in the protective effect of Corynebacterium parvum on encephalomyocarditis virus-induced disease in mice

Treatment of mice with Corynebacterium parvum enhances their resistance to encephalomyocarditis (EMC) virus infection. In EMC-virus-infected mice, pretreated with C. parvum, neither interferon production nor antibody responses were increased. A decrease of virus recovery was observed in cultures of macrophages taken from the peritoneum of mice early after injection of C. parvum and infected with EMC-virus in vitro. The data suggest that C. parvum acts by increasing intrinsic antiviral activity of macrophages.